Anticancer agents

ABSTRACT

Disclosed herein are therapeutic methods of administering compounds that modulate the C—C chemokine receptor type 4 (CCR4) for the treatment of Epstein Bar virus (EBV) positive cancers and malignancies.

This application claims the benefit of U.S. Provisional Application No.62/723,415, filed Aug. 27, 2018 and U.S. Provisional Application No.62/582,284, filed Nov. 6, 2017, the contents of which are incorporatedherein by reference in their entireties and for all purposes.

I. FIELD

Provided herein, inter alia, are methods for treating or managingcertain cancers and malignancies using compounds that modulate the C—Cchemokine receptor type 4 (CCR4), or pharmaceutically acceptable saltsthereof. For example, provided herein are methods in which a CCR4modulator is administered alone or in combination with one or moreanti-cancer agents to treat certain cancers and malignancies. Inaddition, provided herein are pharmaceutical compositions for use insuch methods.

II. BACKGROUND

Cancer is a major worldwide public health problem; in the United Statesalone, approximately 570,000 cancer-related deaths were expected in2005. See, e.g., Jemal et al., CA Cancer J. Clin. 55(1):10-30 (2005).The incidence of cancer continues to climb as the general populationages and new forms of cancer develop.

The Epstein-Barr virus (EBV) is a ubiquitous herpesvirus firstdiscovered as the causative agent of Burkitt's Lymphoma. EBV wassubsequently found to have a very high prevalence, with over 95% of theadult population infected. Infections are generally asymptomatic, butEBV can be the cause of infectious mononucleosis. EBV-positivity hasalso been associated with a variety of cancers, including variouslymphomas, nasopharyngeal carcinoma (NPC), and gastric carcinoma(Hjalgrim, H., Friborg, J. and Melbye, M. 2007. Human Herpesviruses).

For many years researchers have tried to boost the immune response tofight cancer. Though earlier interventions had limited success, therecent use of antibodies such as anti-CTLA-4 and anti-PD-1/PD-L1, alsoknown as immune checkpoint inhibitors (CPIs), has resulted in meaningfulantitumor immune responses in multiple types of cancer (Pardoll, 2012;Sharma, 2015; Shin, 2015).

Tumors are capable of adapting, co-opting natural immune suppressivemechanisms to evade detection by the immune system (Hanahan, 2011; Dunn,2002). An important way that cancers do this is by recruiting andsubverting immune suppressive lymphocytes known as regulatory T cells(T_(reg)). While these suppressive cells help keep immune responses toforeign antigens such as viruses, commensal bacteria, and foreign bodiesin check and limit autoimmune disease, T_(reg) can also interfere withimmune surveillance and allow tumors to evade eradication by the immunesystem (Chaudrhy, 2013; Nishikawa, 2014; Tanaka, 2017).

Numerous studies of human cancers have found T_(reg) accumulation in andaround tumors, which can preclude cytotoxic (effector) T cells (T_(eff))from or inhibit killing tumor cells (Fridman, 2017). Increased T_(reg)numbers in tumors, or a reduced ratio of T_(eff) to T_(reg), correlateswith poor patient prognosis in many cancers, including melanoma, lungand breast cancers (Fridman, 2011; Gobert, 2009; Bates, 2006; Curiel,2004). Data such as these have triggered research into curbing T_(reg)cell activity in an effort to initiate or amplify a therapeuticantitumor immune response. By removing their suppressive effects on anotherwise effective antitumor response, a therapy targeting T_(reg)cells may help eradicate tumors.

Strategies to suppress T_(reg) cells have included modulating cytokinesignaling, depletion with antibodies, or treatment with cytotoxicagents. However, these approaches frequently impact other cellpopulations required for robust immune responses and can trigger sideeffects due to interference with the normal role of T_(reg) cells inhealthy tissues (Kurose, 2015). An alternative approach is to suppressthe recruitment of T_(reg) to the tumor microenvironment (TME).

Systemic circulation of leukocytes is an important factor enablingimmune surveillance. Chemokines are small secreted proteins which formgradients to attract subsets of leukocytes from the circulation in atissue-specific manner (Solari, 2015). To enable recruitment to varioustissues, T_(reg) express a number of chemokine receptors, thoughpredominantly the C—C chemokine receptor type 4 (CCR4) (Lellem, 2001;Hirahara, 2006). CCR4 is a G-protein coupled receptor (GPCR) thatselectively binds the chemokine ligands CCL17 (TARC) and CCL22 (MDC),and this ligand binding plays a key role in the recruitment of T_(reg)and their accumulation in the TME (Curiel, 2004; Gobert, 2009; Li,2013). As such, CCR4 may be an ideal target to selectively block T_(reg)cell recruitment into the TME. CCR4 antagonism may enable the immunesystem to elicit a more robust antitumor response, particularly whencombined with other immunomodulatory agents.

The EBV latent protein LMP1 may lead to expression of CCL17 and CCL22(Nakayama et. al. J Virol, 2004; Takegawa et al Cancer Sci 2008).T_(reg) are increased in EBV-associated gastric carcinoma as compared toEBV-negative gastric carcinoma (Zhang et al Sci. Reports, 2015), and iscorrelated with higher production of CCL22 in EBV+ gastric carcinoma.Nasopharyngeal carcinoma is associated with EBV (Neparidze, N. and Lacy,J. 2014. Malignancies associated with Epstein-Barr Virus: Pathobiology,Clinical Features, and Evolving Treatments. Clinical advances inhematology & oncology: H&O. 12, 6 (2014), 358-71), and there is anincreasing number of T_(reg) in NPC with increasing stage (Ren et al,Clinical Onc and Cancer Res, 2011).

III. SUMMARY

In one aspect, provided herein are methods for treating or managingEBV-associated cancers using compounds having formulae (I), (II), (III),(IV), or (V), or a salt, solvate, or hydrate thereof.

In embodiments, the compounds used in the methods disclosed herein, aredisclosed in U.S. patent application Ser. No. 15/662,861 filed Jul. 28,2017 of Beck et al. (e.g., for example, compounds of Formulae I throughVII), which are incorporated herein by reference in its entirety for allpurposes. In embodiments, the compounds have the chemical structureaccording to Formula I herein.

In embodiments, the compounds used in the methods disclosed herein, aredisclosed in U.S. patent application Ser. No. 15/700,040 filed Sep. 8,2017 of Beck et al. (e.g., for example, compounds of Formulae I throughX), which are incorporated herein by reference in its entirety for allpurposes. In embodiments, the compounds have the chemical structureaccording to Formula II herein.

In embodiments, the compounds used in the methods disclosed herein, aredisclosed in U.S. Patent Application 62/481,515 filed Apr. 4, 2017 ofBeck et al. (e.g., for example, compounds of Formulae I through VI),which are incorporated herein by reference in its entirety for allpurposes. In embodiments, the compounds have the chemical structureaccording to Formula III herein.

In embodiments, compounds used in the methods disclosed herein, aredisclosed in U.S. Patent Application 62/622,774 filed Jan. 26, 2018, ofRobles-Resendiz et al. (e.g., for example, compounds of Formulae Ithrough VII), which are incorporated herein by reference in its entiretyfor all purposes. In embodiments, the compounds have the chemicalstructure according to Formula IV herein.

In embodiments, compounds used in the methods disclosed herein, aredisclosed in U.S. Patent Application 62/622,771 filed Jan. 26, 2018, ofJackson et al. (e.g., for example, compounds of Formula I), which areincorporated herein by reference in its entirety for all purposes. Inembodiments, the compound have the chemical structure according toFormula V herein.

In embodiments, the CCR4 modulator is a compound disclosed in one of thefollowing published patent applications: Hobbs et al, US 2012/0015932;Cheshire et al, US 2010/0144759; Cheshire et al, US 2008/0293742;Cheshire US 2006/0189613; Mete et al, US 2006/0128723; Harrison et al,US 2006/0122195; Habashita et al, US 2006/0004010; Collins et al, US2004/0039035; Collins et al, US 2003/0018022; Collins et al, US2002/0173524; Dairaghi et al, US 2002/0132836; U.S. Pat. Nos. 5,300,498;6,509,357; US 2003/149018; WO 01/005758; WO 03/051876; WO 97/042174; WO2006/101456; WO 2007/065683; WO 2007/065924; WO 2007/115231; WO2008/045529; WO 2008/094575; WO 2008/094602; WO 2010/118367; and WO2013/082429, the CCR4 modulating compounds disclosed in which areincorporated herein by reference.

In embodiments, the CCR4 modulator is an antibody disclosed in one ofthe following published patent applications: Marasco et al. US2017/0290911; Lin et al. US 2017/0088627; Marasco et al. US2016/0185865; Ishii et al. US 2015/0147321; shiara et al. US2013/0295045; Wu et al. US 2007/0031896; shiara et al. US 2007/0020263;and Iida et al. US 2005/0287138, the CCR4 binding antibodies disclosedin which are incorporated herein by reference.

In embodiments, the EBV-associated cancer is a solid tumor. In oneembodiment, the EBV-associated cancer is relapsed or refractory. Inanother embodiment, the methods of the invention are for treatingEBV-associated cancers. In one embodiment, the EBV-associated cancer isnasopharyngeal carcinoma. In one embodiment, the EBV-associated canceris gastric carcinoma. In embodiments, the EBV-associated cancer is alymphoproliferative disorder (e.g. Burkitt's lymphoma, Hodgkin lymphoma,diffuse large B-cell lymphoma, NK/T cell leukemia or lymphoma, etc.).

In embodiments, a compound of formulae (I), (II), (III), (IV), or (V),or a salt, solvate, or hydrate thereof is administered orally orparenterally. In one embodiment, a compound of formulae (I), (II),(III), (IV), or (V), or a salt, solvate, or hydrate thereof isadministered orally. In embodiments, a compound of formulae (I), (II),(III), (IV), or (V), or a salt, solvate, or hydrate thereof isadministered to a subject in need thereof for a sustained period oftime. In embodiments, a compound of formulae (I), (II), (III), (IV), or(V), or a salt, solvate, or hydrate thereof is administered to a subjectin need thereof cyclically (e.g., dosing for one or more days, followedby a resting period). In embodiments, a compound of formulae (I), (II),(III), (IV), or (V), or a salt, solvate, or hydrate thereof isadministered to a subject in need thereof over multiple dosing cycles.In one embodiment, the additional anti-cancer agent is administeredorally or parenterally. In one embodiment, a compound of formulae (I),(II), (III), (IV), or (V), or a salt, solvate, or hydrate thereof isadministered via the same route as the one or more additionalanti-cancer agent(s). In one embodiment, a compound of formulae (I),(II), (III), (IV), or (V), or a salt, solvate, or hydrate thereof isadministered via a different route as the one or more additionalanti-cancer agent(s) (e.g., one administered orally and the otheradministered parenterally).

In embodiments, a compound of formulae (I), (II), (III), (IV), or (V),or a salt, solvate, or hydrate thereof is administered in a particulardosing cycle. In one embodiment, a compound of formulae (I), (II),(III), (IV), or (V), or a salt, solvate, or hydrate thereof and the oneor more additional anti-cancer agent(s) (including, but not limited to,romidepsin, carboplatin, paclitaxel, or Abraxane®) are co-administeredin a particular dosing cycle. In particular embodiments, a compound offormulae (I), (II), (III), (IV), or (V), or a salt, solvate, or hydratethereof is first administered to a subject in need thereof for one ormore days (e.g., for 7 days or more), and the one or more additionalanti-cancer agent(s) is/are administered to the subject (e.g., startingon Day 8 or later of the treatment cycle). In particular embodiments,when one or more additional anti-cancer agent(s) is/are administered tothe subject, a compound of formulae (I), (II), (III), (IV), or (V), or asalt, solvate, or hydrate thereof is also administered to the subject.In particular embodiments, when one or more additional anti-canceragent(s) is/are administered to the subject, a compound of formulae (I),(II), (III), (IV), or (V), or a salt, solvate, or hydrate thereof is notadministered to the subject simultaneously.

In embodiments, a compound of formulae (I), (II), (III), (IV), or (V),or a salt, solvate, or hydrate thereof is administered alone as a singleagent to a subject in need thereof. In one embodiment, a compound offormulae (I), (II), (III), (IV), or (V), or a salt, solvate, or hydratethereof is administered in combination with one or more additionalanti-cancer agent(s), including, but not limited to, romidepsin,carboplatin, paclitaxel, or Abraxane® (paclitaxel protein-boundparticles), among others. In one embodiment, the additional anti-canceragent is an alkylating agent, a cytotoxic agent, an anti-angiogenicagent, an anti-tubulin agent, an anti-metabolite, a kinase inhibitor, abiologics agent, or any other known anti-cancer agent (e.g., ananti-cancer agent provided herein elsewhere). In certain embodiments, inaddition to a compound of formulae (I), (II), (III), (IV), or (V), or asalt, solvate, or hydrate thereof or one or more additional anti-canceragent(s), an anti-emetic is administered to a subject in need thereof.In a particular embodiment, a compound of formulae (I), (II), (III),(IV), or (V), or a salt, solvate, or hydrate thereof is administered incombination with carboplatin. In another embodiment, a compound offormulae (I), (II), (III), (IV), or (V), or a salt, solvate, or hydratethereof is administered in combination with Abraxane®. In anotherembodiment, a compound of formulae (I), (II), (III), (IV), or (V), or asalt, solvate, or hydrate thereof is administered in combination withromidepsin. In one embodiment, a compound of formulae (I), (II), (III),(IV), or (V), or a salt, solvate, or hydrate thereof is administered incombination with one or more additional immunomodulatory agent(s)including, but not limited to, (1) antibodies targeting PD-1, PD-L1,CTLA-4, CD40, GITR, LAG3 and/or CD137; (2) inhibitors of IDO, TDO, A2AR,A2BR, CD39, CD73, USP7, GCN2 and/or HPK1 (3) activators of innateimmunity including TLRs, STING, cGAS, etc.; (4) cellular immunotherapiesincluding adoptive T cell transfer, Chimeric Antigen Receptor (CAR)-Tcell transfer, NK cell therapies, etc.; (5) vaccine strategies includingbacterial, viral, or synthetic vaccination; (6) oncolytic viraltherapies and/or (7) bi-specific/tri-specific T cell engagers.

In one aspect, provided herein is a pharmaceutical compositioncomprising a compound of formulae (I), (II), (III), (IV), or (V), or asalt, solvate, or hydrate thereof for use in any of the methodsdescribed herein.

In embodiments, a compound of formulae (I), (II), (III), (IV), or (V),or a salt, solvate, or hydrate thereof is formulated in an oral dosageform provided herein (e.g., a tablet or a capsule).

In embodiments, provided herein are pharmaceutical compositionscomprising a compound of formulae (I), (II), (III), (IV), or (V), or asalt, solvate, or hydrate thereof, wherein the composition releases theactive pharmaceutical ingredient (API) substantially in the stomach uponoral administration. In one embodiment, provided herein arepharmaceutical compositions comprising a compound of formulae (I), (II),(III), (IV), or (V), or a salt, solvate, or hydrate thereof, wherein thecomposition releases the API substantially in the stomach and/or theupper intestine upon oral administration. In one embodiment, providedherein are pharmaceutical compositions comprising a compound of formulae(I), (II), (III), (IV), or (V), or a salt, solvate, or hydrate thereof,wherein the composition releases the API substantially in the stomach,the upper intestine and/or the lower intestine upon oral administration.Also provided are methods for making the compositions, and methods forusing the compositions to treat or manage diseases and disordersincluding EBV-associated cancer, disorders related to abnormal cellproliferation, solid tumors, and hematologic disorders.

In one aspect, provided herein is a kit comprising a compound offormulae (I), (II), (III), (IV), or (V), or a salt, solvate, or hydratethereof for use in any of the methods described herein.

IV. DETAILED DESCRIPTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art. All publications and patents referred to herein areincorporated by reference herein in their entireties.

V. DEFINITIONS

As used in the specification, the term “about” or “approximately” meansan acceptable error for a particular value as determined by one ofordinary skill in the art, which depends in part on how the value ismeasured or determined. In certain embodiments, the term “about” or“approximately” means within 1, 2, 3, or 4 standard deviations. Incertain embodiments, the term “about” or “approximately” means within30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%,or 0.05% of a given value or range.

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e., unbranched) or branchedcarbon chain (or carbon), or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include mono-, di- andmultivalent radicals. The alkyl may include a designated number ofcarbons (e.g., C₁-C₁₀ means one to ten carbons). Alkyl is an uncyclizedchain. Examples of saturated hydrocarbon radicals include, but are notlimited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, forexample, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Anunsaturated alkyl group is one having one or more double bonds or triplebonds. Examples of unsaturated alkyl groups include, but are not limitedto, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers. An alkoxy is an alkylattached to the remainder of the molecule via an oxygen linker (—O—). Analkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynylmoiety. An alkyl moiety may be fully saturated. An alkenyl may includemore than one double bond and/or one or more triple bonds in addition tothe one or more double bonds. An alkynyl may include more than onetriple bond and/or one or more double bonds in addition to the one ormore triple bonds.

The term “alkylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkyl, asexemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (oralkylene) group will have from 1 to 24 carbon atoms, with those groupshaving 10 or fewer carbon atoms being preferred herein. A “lower alkyl”or “lower alkylene” is a shorter chain alkyl or alkylene group,generally having eight or fewer carbon atoms. The term “alkenylene,” byitself or as part of another substituent, means, unless otherwisestated, a divalent radical derived from an alkene.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcombinations thereof, including at least one carbon atom and at leastone heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen andsulfur atoms may optionally be oxidized, and the nitrogen heteroatom mayoptionally be quaternized. The heteroatom(s) (e.g., N, S, Si, or P) maybe placed at any interior position of the heteroalkyl group or at theposition at which the alkyl group is attached to the remainder of themolecule. Heteroalkyl is an uncyclized chain. Examples include, but arenot limited to: —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃,—Si(CH₃)₃, —CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and—CN. Up to two or three heteroatoms may be consecutive, such as, forexample, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. A heteroalkyl moiety mayinclude one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moietymay include two optionally different heteroatoms (e.g., O, N, S, Si, orP). A heteroalkyl moiety may include three optionally differentheteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may includefour optionally different heteroatoms (e.g., O, N, S, Si, or P). Aheteroalkyl moiety may include five optionally different heteroatoms(e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8optionally different heteroatoms (e.g., O, N, S, Si, or P).

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, a divalent radical derivedfrom heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—. As describedabove, heteroalkyl groups, as used herein, include those groups that areattached to the remainder of the molecule through a heteroatom, such as—C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where“heteroalkyl” is recited, followed by recitations of specificheteroalkyl groups, such as —NR′R″ or the like, it will be understoodthat the terms heteroalkyl and —NR′R″ are not redundant or mutuallyexclusive. Rather, the specific heteroalkyl groups are recited to addclarity. Thus, the term “heteroalkyl” should not be interpreted hereinas excluding specific heteroalkyl groups, such as —NR′R″ or the like.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, mean, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl andheterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, aheteroatom can occupy the position at which the heterocycle is attachedto the remainder of the molecule. Examples of cycloalkyl include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a“heterocycloalkylene,” alone or as part of another substituent, means adivalent radical derived from a cycloalkyl and heterocycloalkyl,respectively. “Cycloalkyl” is also meant to refer to bicyclic andpolycyclic hydrocarbon rings such as, for example,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “acyl” means, unless otherwise stated, —C(O)R where R is asubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent, which can be a single ring ormultiple rings (preferably from 1 to 3 rings) that are fused together(i.e., a fused ring aryl) or linked covalently. A fused ring aryl refersto multiple rings fused together wherein at least one of the fused ringsis an aryl ring. The term “heteroaryl” refers to aryl groups (or rings)that contain at least one heteroatom such as N, O, or S, wherein thenitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. Thus, the term “heteroaryl” includesfused ring heteroaryl groups (i.e., multiple rings fused togetherwherein at least one of the fused rings is a heteroaromatic ring). A5,6-fused ring heteroarylene refers to two rings fused together, whereinone ring has 5 members and the other ring has 6 members, and wherein atleast one ring is a heteroaryl ring. Likewise, a 6,6-fused ringheteroarylene refers to two rings fused together, wherein one ring has 6members and the other ring has 6 members, and wherein at least one ringis a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to tworings fused together, wherein one ring has 6 members and the other ringhas 5 members, and wherein at least one ring is a heteroaryl ring. Aheteroaryl group can be attached to the remainder of the moleculethrough a carbon or heteroatom. Non-limiting examples of aryl andheteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl,pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl,oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl,benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl,indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl,quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl,2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl,5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. Substituents for each of the above notedaryl and heteroaryl ring systems are selected from the group ofacceptable substituents described below. An “arylene” and a“heteroarylene,” alone or as part of another substituent, mean adivalent radical derived from an aryl and heteroaryl, respectively. Aheteroaryl group substituent may be —O— bonded to a ring heteroatomnitrogen.

Spirocyclic rings are two or more rings wherein adjacent rings areattached through a single atom. The individual rings within spirocyclicrings may be identical or different. Individual rings in spirocyclicrings may be substituted or unsubstituted and may have differentsubstituents from other individual rings within a set of spirocyclicrings. Possible substituents for individual rings within spirocyclicrings are the possible substituents for the same ring when not part ofspirocyclic rings (e.g. substituents for cycloalkyl or heterocycloalkylrings). Spirocylic rings may be substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heterocycloalkylene andindividual rings within a spirocyclic ring group may be any of theimmediately previous list, including having all rings of one type (e.g.all rings being substituted heterocycloalkylene wherein each ring may bethe same or different substituted heterocycloalkylene). When referringto a spirocyclic ring system, heterocyclic spirocyclic rings means aspirocyclic rings wherein at least one ring is a heterocyclic ring andwherein each ring may be a different ring. When referring to aspirocyclic ring system, substituted spirocyclic rings means that atleast one ring is substituted and each substituent may optionally bedifferent.

The symbol “

” denotes the point of attachment of a chemical moiety to the remainderof a molecule or chemical formula.

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom.

The term “alkylarylene” as an arylene moiety covalently bonded to analkylene moiety (also referred to herein as an alkylene linker). Inembodiments, the alkylarylene group has the formula:

An alkylarylene moiety may be substituted (e.g. with a substituentgroup) on the alkylene moiety or the arylene linker (e.g. at carbons 2,3, 4, or 6) with halogen, oxo, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂CH₃—SO₃H, —OSO₃H, —SO₂NH₂,□NHNH₂, □ONH₂, □NHC(O)NHNH₂, substituted or unsubstituted C₁-C₅ alkyl orsubstituted or unsubstituted 2 to 5 membered heteroalkyl). Inembodiments, the alkylarylene is unsubstituted.

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “cycloalkyl,”“heterocycloalkyl,” “aryl,” and “heteroaryl”) includes both substitutedand unsubstituted forms of the indicated radical. Preferred substituentsfor each type of radical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, □NR′NR″R′″,□ONR′R″, □NR′C(O)NR″NR′″R″″, —CN, —NO₂, —NR′SO₂R″, —NR′C(O)R″,—NR′C(O)—OR″, —NR′OR″, in a number ranging from zero to (2m′+1), wherem′ is the total number of carbon atoms in such radical. R, R′, R″, R′″,and R″″ each preferably independently refer to hydrogen, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl (e.g., aryl substituted with 1-3 halogens),substituted or unsubstituted heteroaryl, substituted or unsubstitutedalkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When acompound described herein includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, R′″,and R″″ group when more than one of these groups is present. When R′ andR″ are attached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example,—NR′R″ includes, but is not limited to, 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups including carbon atoms bound to groups other than hydrogengroups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g.,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″,—S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, □NR′NR″R′″, □ONR′R″,□NR′C(O)NR″NR′″R″″, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy,and fluoro(C₁-C₄)alkyl, —NR′SO₂R″, —NR′C(O)R″, —NR′C(O)—OR″, —NR′OR″, ina number ranging from zero to the total number of open valences on thearomatic ring system; and where R′, R″, R′″, and R″″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl. When a compound described herein includes more than one Rgroup, for example, each of the R groups is independently selected asare each R′, R″, R′″, and R″″ groups when more than one of these groupsis present.

Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl,heteroaryl, cycloalkylene, heterocycloalkylene, arylene, orheteroarylene) may be depicted as substituents on the ring rather thanon a specific atom of a ring (commonly referred to as a floatingsubstituent). In such a case, the substituent may be attached to any ofthe ring atoms (obeying the rules of chemical valency) and in the caseof fused rings or spirocyclic rings, a substituent depicted asassociated with one member of the fused rings or spirocyclic rings (afloating substituent on a single ring), may be a substituent on any ofthe fused rings or spirocyclic rings (a floating substituent on multiplerings). When a substituent is attached to a ring, but not a specificatom (a floating substituent), and a subscript for the substituent is aninteger greater than one, the multiple substituents may be on the sameatom, same ring, different atoms, different fused rings, differentspirocyclic rings, and each substituent may optionally be different.Where a point of attachment of a ring to the remainder of a molecule isnot limited to a single atom (a floating substituent), the attachmentpoint may be any atom of the ring and in the case of a fused ring orspirocyclic ring, any atom of any of the fused rings or spirocyclicrings while obeying the rules of chemical valency. Where a ring, fusedrings, or spirocyclic rings contain one or more ring heteroatoms and thering, fused rings, or spirocyclic rings are shown with one more floatingsubstituents (including, but not limited to, points of attachment to theremainder of the molecule), the floating substituents may be bonded tothe heteroatoms. Where the ring heteroatoms are shown bound to one ormore hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and athird bond to a hydrogen) in the structure or formula with the floatingsubstituent, when the heteroatom is bonded to the floating substituent,the substituent will be understood to replace the hydrogen, whileobeying the rules of chemical valency.

Two or more substituents may optionally be joined to form aryl,heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-calledring-forming substituents are typically, though not necessarily, foundattached to a cyclic base structure. In one embodiment, the ring-formingsubstituents are attached to adjacent members of the base structure. Forexample, two ring-forming substituents attached to adjacent members of acyclic base structure create a fused ring structure. In anotherembodiment, the ring-forming substituents are attached to a singlemember of the base structure. For example, two ring-forming substituentsattached to a single member of a cyclic base structure create aspirocyclic structure. In yet another embodiment, the ring-formingsubstituents are attached to non-adjacent members of the base structure.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally form a ring of the formula -T-C(O)—(CRR′)_(q)—U—, whereinT and U are independently —NR—, —O—, —CRR′—, or a single bond, and q isan integer of from 0 to 3. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′—, or asingle bond, and r is an integer of from 1 to 4. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CRR′)_(s)—X′— (C″R″R′″)_(d)—, where s and d are independentlyintegers of from 0 to 3, and X′ is —O—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″, and R′″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant toinclude oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), andsilicon (Si).

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

(A) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, □NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃,—OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl), and(B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,substituted with at least one substituent selected from:(i) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃,—OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl), and(ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,substituted with at least one substituent selected from:(a) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃,—OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl), and(b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,substituted with at least one substituent selected from: oxo, halogen,—CCl₃, —CBr₃, —CF₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCHBr₂, —OCHI₂, —OCHF₂, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl,C₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

A “size-limited substituent” or “size-limited substituent group,” asused herein, means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl.

A “lower substituent” or “lower substituent group,” as used herein,means a group selected from all of the substituents described above fora “substituent group,” wherein each substituted or unsubstituted alkylis a substituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl.

In some embodiments, each substituted group described in the compoundsherein is substituted with at least one substituent group. Morespecifically, in some embodiments, each substituted alkyl, substitutedheteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl,substituted aryl, substituted heteroaryl, substituted alkylene,substituted heteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene described in the compounds herein are substituted with atleast one substituent group. In other embodiments, at least one or allof these groups are substituted with at least one size-limitedsubstituent group. In other embodiments, at least one or all of thesegroups are substituted with at least one lower substituent group.

In other embodiments of the compounds herein, each substituted orunsubstituted alkyl may be a substituted or unsubstituted C₁-C₂₀ alkyl,each substituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl. In someembodiments of the compounds herein, each substituted or unsubstitutedalkylene is a substituted or unsubstituted C₁-C₂₀ alkylene, eachsubstituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 20 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₈cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 8 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 10 membered heteroarylene.

In some embodiments, each substituted or unsubstituted alkyl is asubstituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl. In some embodiments, each substituted orunsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene,each substituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 8 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₇cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 7 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 9 membered heteroarylene. In someembodiments, the compound is a chemical species set forth in theExamples section, FIGURES, or tables below.

Certain compounds of the present invention possess asymmetric carbonatoms (optical or chiral centers) or double bonds; the enantiomers,racemates, diastereomers, tautomers, geometric isomers, stereoisomericforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)-for amino acids, and individual isomers areencompassed within the scope of the present invention. The compounds ofthe present invention do not include those that are known in art to betoo unstable to synthesize and/or isolate. The present invention ismeant to include compounds in racemic and optically pure forms.Optically active (R)- and (S)-, or (D)- and (L)-isomers may be preparedusing chiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic bondsor other centers of geometric asymmetry, and unless specified otherwise,it is intended that the compounds include both E and Z geometricisomers.

As used herein, the term “isomers” refers to compounds having the samenumber and kind of atoms, and hence the same molecular weight, butdiffering in respect to the structural arrangement or configuration ofthe atoms.

The term “tautomer,” as used herein, refers to one of two or morestructural isomers which exist in equilibrium and which are readilyconverted from one isomeric form to another.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areencompassed within the scope of the present invention.

It should be noted that throughout the application that alternatives arewritten in Markush groups, for example, each amino acid position thatcontains more than one possible amino acid. It is specificallycontemplated that each member of the Markush group should be consideredseparately, thereby comprising another embodiment, and the Markush groupis not to be read as a single unit.

“Analog,” or “analogue” is used in accordance with its plain ordinarymeaning within Chemistry and Biology and refers to a chemical compoundthat is structurally similar to another compound (i.e., a so-called“reference” compound) but differs in composition, e.g., in thereplacement of one atom by an atom of a different element, or in thepresence of a particular functional group, or the replacement of onefunctional group by another functional group, or the absolutestereochemistry of one or more chiral centers of the reference compound.Accordingly, an analog is a compound that is similar or comparable infunction and appearance but not in structure or origin to a referencecompound.

The terms “a” or “an,” as used in herein means one or more. In addition,the phrase “substituted with a[n],” as used herein, means the specifiedgroup may be substituted with one or more of any or all of the namedsubstituents. For example, where a group, such as an alkyl or heteroarylgroup, is “substituted with an unsubstituted C₁-C₂₀ alkyl, orunsubstituted 2 to 20 membered heteroalkyl,” the group may contain oneor more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2to 20 membered heteroalkyls.

Moreover, where a moiety is substituted with an R substituent, the groupmay be referred to as “R-substituted.” Where a moiety is R-substituted,the moiety is substituted with at least one R substituent and each Rsubstituent is optionally different. Where a particular R group ispresent in the description of a chemical genus (such as Formula (I)), aRoman alphabetic symbol may be used to distinguish each appearance ofthat particular R group. For example, where multiple R¹³ substituentsare present, each R¹³ substituent may be distinguished as R^(13A),R^(13B), R^(13C), R^(13D), etc., wherein each of R^(13A), R^(13B),R^(13C), R^(13D), etc. is defined within the scope of the definition ofR¹³ and optionally differently.

A “detectable moiety” as used herein refers to a moiety that can becovalently or noncovalently attached to a compound or biomolecule thatcan be detected for instance, using techniques known in the art. Inembodiments, the detectable moiety is covalently attached. Thedetectable moiety may provide for imaging of the attached compound orbiomolecule. The detectable moiety may indicate the contacting betweentwo compounds. Exemplary detectable moieties are fluorophores,antibodies, reactive dies, radio-labeled moieties, magnetic contrastagents, and quantum dots. Exemplary fluorophores include fluorescein,rhodamine, GFP, coumarin, FITC, Alexa fluor, Cy3, Cy5, BODIPY, andcyanine dyes. Exemplary radionuclides include Fluorine-18, Gallium-68,and Copper-64. Exemplary magnetic contrast agents include gadolinium,iron oxide and iron platinum, and manganese.

Descriptions of compounds of the present invention are limited byprinciples of chemical bonding known to those skilled in the art.Accordingly, where a group may be substituted by one or more of a numberof substituents, such substitutions are selected so as to comply withprinciples of chemical bonding and to give compounds which are notinherently unstable and/or would be known to one of ordinary skill inthe art as likely to be unstable under ambient conditions, such asaqueous, neutral, and several known physiological conditions. Forexample, a heterocycloalkyl or heteroaryl is attached to the remainderof the molecule via a ring heteroatom in compliance with principles ofchemical bonding known to those skilled in the art thereby avoidinginherently unstable compounds.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” refer to the eradication or amelioration of adisease or disorder, or of one or more symptoms associated with thedisease or disorder. In certain embodiments, the terms refer tominimizing the spread or worsening of the disease or disorder resultingfrom the administration of one or more prophylactic or therapeuticagents to a subject with such a disease or disorder. In someembodiments, the terms refer to the administration of a compound ordosage form provided herein, with or without one or more additionalactive agent(s), after the onset of symptoms of the particular disease.

In some embodiments, the terms refer to the prevention of the onset,recurrence or spread of a disease or disorder, or of one or moresymptoms thereof. In certain embodiments, the terms refer to treatmentprior to the onset of symptoms, particularly to subjects at risk ofdisease or disorders provided herein. The terms encompass the inhibitionor reduction of a symptom of the particular disease. Subjects withfamilial history of a disease are potential candidates for preventiveregimens in certain embodiments. In addition, subjects who have ahistory of recurring symptoms are also potential candidates forprevention. In this regard, the term “prevention” may be interchangeablyused with the term “prophylactic treatment.”

As used herein, and unless otherwise specified, the terms “manage,”“managing” and “management” refer to preventing or slowing theprogression, spread or worsening of a disease or disorder, or of one ormore symptoms thereof. Often, the beneficial effects that a subjectderives from a prophylactic and/or therapeutic agent do not result in acure of the disease or disorder. In this regard, the term “managing”encompasses treating a subject who had suffered from the particulardisease in an attempt to prevent or minimize the recurrence of thedisease.

As used herein, “amelioration” of the symptoms of a particular disorderby administration of a particular pharmaceutical composition refers toany lessening, whether permanent or temporary, lasting or transient,that can be attributed to or associated with administration of thecomposition.

As used herein, and unless otherwise specified, the terms“therapeutically effective amount” and “effective amount” of a compoundmean an amount sufficient to provide a therapeutic benefit in thetreatment or management of a disease or disorder, or to delay orminimize one or more symptoms associated with the disease or disorder. A“therapeutically effective amount” and “effective amount” of a compoundmean an amount of therapeutic agent, alone or in combination with one ormore other agent(s), which provides a therapeutic benefit in thetreatment or management of the disease or disorder. The terms“therapeutically effective amount” and “effective amount” can encompassan amount that improves overall therapy, reduces or avoids symptoms orcauses of disease or disorder, or enhances the therapeutic efficacy ofanother therapeutic agent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease or disorder, or prevent its recurrence. A prophylacticallyeffective amount of a compound means an amount of therapeutic agent,alone or in combination with one or more other agent(s), which providesa prophylactic benefit in the prevention of the disease. The term“prophylactically effective amount” can encompass an amount thatimproves overall prophylaxis or enhances the prophylactic efficacy ofanother prophylactic agent.

As used herein, and unless otherwise specified, the term “subject” isdefined herein to include animals such as mammals, including, but notlimited to, primates (e.g., humans), cows, sheep, goats, horses, dogs,cats, rabbits, rats, mice, and the like. In specific embodiments, thesubject is a human. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, such as a human.

As used herein, and unless otherwise specified, the term “tumor” refersto all neoplastic cell growth and proliferation, whether malignant orbenign, and all pre-cancerous and cancerous cells and tissues.“Neoplastic,” as used herein, refers to any form of dysregulated orunregulated cell growth, whether malignant or benign, resulting inabnormal tissue growth. Thus, “neoplastic cells” include malignant andbenign cells having dysregulated or unregulated cell growth.

As used herein, and unless otherwise specified, the terms “cancer” and“cancerous” refer to or describe the physiological condition in mammalsthat is typically characterized by unregulated cell growth. Examples ofcancer include, but are not limited to blood-borne (e.g., lymphoma,leukemia) and solid tumors.

As used herein, and unless otherwise specified, the term “proliferative”disorder or disease refers to unwanted cell proliferation of one or moresubset of cells in a multicellular organism resulting in harm (i.e.,discomfort or decreased life expectancy) to the multicellular organism.For example, as used herein, proliferative disorder or disease includesneoplastic disorders and other proliferative disorders.

As used herein, and unless otherwise specified, the term “relapsed”refers to a situation where a subject, that has had a remission ofcancer after a therapy, has a return of cancer cells.

As used herein, and unless otherwise specified, the term “refractory” or“resistant” refers to a circumstance where a subject, even afterintensive treatment, has residual cancer cells in the body.

As used herein, and unless otherwise specified, the term “drugresistance” refers to the condition when a disease does not respond tothe treatment of a drug or drugs. Drug resistance can be eitherintrinsic, which means the disease has never been responsive to the drugor drugs, or it can be acquired, which means the disease ceasesresponding to a drug or drugs that the disease had previously respondedto. In certain embodiments, drug resistance is intrinsic. In certainembodiments, the drug resistance is acquired.

As used herein, the terms “Epstein-Barr virus” and “EBV” are usedinterchangeably herein and refer to a virus that is also sometimescalled human herpesvirus 4 (HHV-4). This virus is one of eight knownhuman herpesvirus types in the herpes family, and is one of the mostcommon viruses in humans. The virus is best known as the cause ofinfectious mononucleosis (glandular fever). It is also associated withparticular forms of cancer, such as Hodgkin's lymphoma, Burkitt'slymphoma, gastric cancer, nasopharyngeal carcinoma, and conditionsassociated with human immunodeficiency virus (HIV), such as hairyleukoplakia and central nervous system lymphomas.

As used herein, and unless otherwise specified, the terms“EBV-associated”, “EBV positive” and “EBV+”, when use in describing acancer or malignancy, refers to a cancer or malignancy that has beenlinked to the Epstein-Barr virus (EBV), namely a cancer that containsthe EBV genome, or expresses one or more genes from the EBV genome inthe form of miRNA, mRNA or protein.

As used herein, and unless otherwise specified, the terms “C—C chemokinereceptor type 4” and “CCR4” refer to a protein (including homologs,isoforms, and functional fragments thereof) and is a high affinityreceptor for the C—C type chemokines (e.g., CCL2 (MCP-1), CCL4 (MIP-1),CCL5 (RANTES), CCL17 (TARC), and CCL22 (MDC)). It is referred to by anumber of different names in the scientific literature, including“CC—CKR-4”, “C—C CKR-4”, “K5-5”, “CD194”, “CMKBR4”, “ChemR13”, “HGCN”,and “14099”. The term includes any recombinant or naturally-occurringform of CCR4 variants thereof that maintain CCR4 activity (e.g. withinat least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activitycompared to wildtype CCR4). The term includes any mutant form of CCR4variants (e.g., frameshift mutations) thereof that maintain CCR4activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%,or 100% activity compared to wildtype CCR4). In embodiments, the CCR4protein encoded by the CCR4 gene has the amino acid sequence set forthin or corresponding to Entrez 1233, UniProt P51679, or RefSeq (protein)NP 005499.1. In embodiments, the CCR4 gene has the nucleic acid sequenceset forth in RefSeq (mRNA) NM 005508. In embodiments, the amino acidsequence or nucleic acid sequence is the sequence known at the time offiling of the present application. In embodiments, the sequencecorresponds to GI:5031627. In embodiments, the sequence corresponds toNP_005499.1. In embodiments, the sequence corresponds to NM_005508.4. Inembodiments, the sequence corresponds to GI:48762930. In embodiments,the CCR4 is a human CCR4, such as a human cancer causing CCR4. Thoughfrequently found on dendritic cells, macrophages, NK cells, platelets,and basophils, CCR4 is predominantly associated with T cells. It plays arole in the progression of multiple inflammation-related disorders, and,as described herein, has also been implicated in a number of otherconditions. The genomic sequence of CCR4 is present on chromosome 3(NC_000003.12), and the CCR4 gene is conserved in a number of species,including chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, andzebrafish. The CCR4 polypeptide comprises 360 amino acid residues(NP_005499.1), and, like other chemokine receptors, CCR4 is a Gprotein-coupled receptor found on the surface of leukocytes (see Horuk(1994) Trends Pharm. Sci. 15:159-165).

As used herein, and unless otherwise specified, the term “anti-canceragent,” “anticancer agent” or “cancer therapeutic agent” is meant toinclude anti-proliferative agents and chemotherapeutic agents,including, but not limited to, antimetabolites (e.g., 5-fluoro uracil,methotrexate, azacitidine, decitabine, fludarabine, cytarabine (alsoknown as cytosine arabinoside or Ara-C), and high dose cytarabine),antimicrotubule agents (e.g., vinca alkaloids, such as vincristine andvinblastine; and taxanes, such as paclitaxel and docetaxel), alkylatingagents (e.g., mechlorethamine, chlorambucil, cyclophosphamide,melphalan, carmustine, lomustine, ifosfamide, carmustine, busulfan,cyclophosphamide, dacarbazine, ifosfamide, and nitrosoureas, such asbischloroethylnitrosurea, and hydroxyurea), platinum agents (e.g.,cisplatin, carboplatin, oxaliplatin, satraplatin (JM-216), and CI-973),anthracyclines (e.g., doxorubicin and daunorubicin), antitumorantibiotics (e.g., mitomycin, bleomycin, idarubicin, adriamycin,daunomycin (also known as daunorubicin, rubidomycin, or cerubidine),and, topoisomerase inhibitors (e.g., etoposide, mitoxantrone andcamptothecins), purine antagonists or pyrimidine antagonists (e.g.,6-mercaptopurine, 5-fluorouracil, cytarabine, clofarabine, andgemcitabine), cell maturing agents (e.g., arsenic trioxide andtretinoin), DNA repair enzyme inhibitors (e.g., podophyllotoxines,etoposide, irinotecan, topotecan, and teniposide), enzymes that preventcell survival (e.g., asparaginase and pegaspargase), histone deacetylaseinhibitors (e.g., vorinostat and romidepsin), any other cytotoxic agents(e.g., estramustine phosphate, dexamethasone, prednimustine, andprocarbazine), hormones (e.g., dexamethasone, prednisone,methylprednisolone, tamoxifen, leuprolide, flutamide, and megestrol),monoclonal antibodies (e.g., gemtuzumab ozogamicin, alemtuzumab,rituximab, and yttrium-90-ibritumomab tiuxetan), immuno-modulators(e.g., thalidomide and lenalidomide), Bcr-Abl kinase inhibitors (e.g.,AP23464, AZD0530, CGP76030, PD180970, SKI-606, imatinib, BMS354825(dasatinib), AMN107 (nilotinib), and VX-680), hormone agonists orantagonists, partial agonists or partial antagonists, kinase inhibitors,surgery, radiotherapy (e.g., gamma-radiation, neutron bean radiotherapy,electron beam radiotherapy, proton therapy, brachytherapy, and systemicradioactive isotopes), endocrine therapy, biological response modifiers(e.g., interferons, interleukins, and tumor necrosis factor),hyperthermia and cryotherapy, immune system modulating agents, andagents to attenuate any adverse effects (e.g., antiemetics) and otherapproved chemotherapeutic drugs, including, but not limited to,alkylating drugs (mechlorethamine, chlorambucil, cyclophosphamide,melphalan, and ifosfamide), antimetabolites (cytarabine, high dosecytarabine, and methotrexate), purine antagonists and pyrimidineantagonists (6-mercaptopurine, 5-fluorouracil, cytarabine, andgemcitabine), spindle poisons (vinblastine, vincristine, vinorelbine,docetaxel, and paclitaxel, e.g., Abraxane®), podophyllotoxins(etoposide, irinotecan, and topotecan), antibiotics (daunorubicin,doxorubicin, bleomycin, and mitomycin), nitrosoureas (carmustine andlomustine), inorganic ions (cisplatin and carboplatin), enzymes(asparaginase), and hormones (tamoxifen, leuprolide, flutamide, andmegestrol), imatinib, adriamycin, dexamethasone, and cyclophosphamide.For additional available cancer therapies, see, e.g.,http://www.nci.nih.gov/; for a list of FDA approved oncology drugs, see,e.g., http://www.fda.gov/, The Merck Manual, 18th Ed. 2006, and PDR:Physician Desk Reference 2010, 64th Ed. 2009; the contents of each ofwhich are hereby incorporated by reference in their entireties.

As used herein, and unless otherwise specified, the terms“co-administration” and “in combination with” include the administrationof two or more therapeutic agents simultaneously, concurrently, orsequentially within no specific time limits unless otherwise indicated.In one embodiment, the agents are present in the cell or in thesubject's body at the same time or exert their biological or therapeuticeffect at the same time. In one embodiment, the therapeutic agents arein the same composition or unit dosage form. In other embodiments, thetherapeutic agents are in separate compositions or unit dosage forms. Incertain embodiments, a first agent can be administered prior to (e.g., 5minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before),essentially concomitantly with, or subsequent to (e.g., 5 minutes, 15minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks,4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) theadministration of a second therapeutic agent.

The terms “composition,” “formulation,” and “dosage form,” as usedherein are intended to encompass compositions comprising the specifiedingredient(s) (in the specified amounts, if indicated), as well as anyproduct(s) which result, directly or indirectly, from combination of thespecified ingredient(s) in the specified amount(s). By “pharmaceutical”or “pharmaceutically acceptable” it is meant that any diluent(s),excipient(s) or carrier(s) in the composition, formulation, or dosageform are compatible with the other ingredient(s) and not deleterious tothe recipient thereof. Unless indicated otherwise, the terms“composition,” “formulation,” and “dosage form” are used hereininterchangeably.

As used herein, and unless otherwise specified, the term “immediaterelease,” when used in reference to a composition, formulation, ordosage form provided herein, means that the composition, formulation, ordosage form does not comprise a component (e.g., a coating) that servesto delay the spatial and/or temporal release of some or all of the APIfrom the composition, formulation, or dosage form following oraladministration. In certain embodiments, an immediate releasecomposition, formulation, or dosage form is one that releases the APIsubstantially in the stomach following oral administration. In certainembodiments, an immediate release composition, formulation, or dosageform is one that releases the API substantially in the stomach or theupper intestine following oral administration. In specific embodiments,an immediate release composition, formulation, or dosage form is onethat is not delayed-release. In specific embodiments, an immediaterelease composition, formulation, or dosage form is one that does notcomprise an enteric coating.

As used herein, and unless otherwise specified, the term“non-enteric-coated,” refers to a pharmaceutical composition,formulation, or dosage form that does not comprise a coating intended torelease the active ingredient(s) beyond the stomach (e.g., in theintestine). In certain embodiments, a non-enteric-coated composition,formulation, or dosage form is designed to release the activeingredient(s) substantially in the stomach. In certain embodiments, anon-enteric-coated composition, formulation, or dosage form is designedto release the active ingredient(s) substantially in the stomach and theupper intestine.

As used herein, and unless otherwise specified, the term “substantiallyin the stomach,” when used herein in reference to a composition,formulation, or dosage form provided herein, means that at least about99%, at least about 95%, at least about 90%, at least about 85%, atleast about 80%, at least about 75%, at least about 70%, at least about65%, at least about 60%, at least about 55%, at least about 50%, atleast about 45%, at least about 40%, at least about 35%, at least about30%, at least about 25%, at least about 20%, at least about 15%, or atleast about 10% of a CCR4 modulator is released in the stomach. The term“released in the stomach” and related terms as used herein refer to theprocess whereby a CCR4 modulator is made available for uptake by ortransport across cells lining the stomach and then made available to thebody.

Certain compounds disclosed herein possess asymmetric carbon atoms(optical or chiral centers) or double bonds; the enantiomers, racemates,diastereomers, tautomers, geometric isomers, stereoisomeric forms thatmay be defined, in terms of absolute stereochemistry, as (R)- or (S)-or, as (D)- or (L)-for amino acids, and individual isomers areencompassed within the scope of the present disclosure. The compounds ofthe present disclosure do not include those that are known in art to betoo unstable to synthesize and/or isolate. The presently disclosedcompounds include compounds in racemic and optically pure forms.Optically active (R)- and (S)-, or (D)- and (L)-isomers may be preparedusing chiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic bondsor other centers of geometric asymmetry, and unless specified otherwise,it is intended that the compounds include both E and Z geometricisomers.

It will be apparent to one skilled in the art that certain compounds mayexist in tautomeric forms, all such tautomeric forms of the compoundsbeing within the scope hereof.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope hereof.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by 13C- or 14C-enriched carbonare within the scope hereof.

The compounds of the present disclosure may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present disclosure, whether radioactive or not, areencompassed within the scope of the present disclosure.

As used herein, and unless otherwise specified, the term“pharmaceutically acceptable carrier,” “pharmaceutically acceptableexcipient,” “physiologically acceptable carrier,” or “physiologicallyacceptable excipient” refers to a pharmaceutically-acceptable material,composition, or vehicle, such as, e.g., a liquid or solid filler,diluent, excipient, solvent, or encapsulating material. In oneembodiment, each component is “pharmaceutically acceptable” in the senseof being compatible with the other ingredients of a pharmaceuticalformulation, and suitable for use in contact with the tissue or organ ofhumans and animals without excessive toxicity, irritation, allergicresponse, immunogenicity, or other problems or complications,commensurate with a reasonable benefit/risk ratio. In one embodiment, by“pharmaceutical” or “pharmaceutically acceptable” it is meant that anydiluent(s), excipient(s) or carrier(s) in the composition, formulation,or dosage form are compatible with the other ingredient(s) and notdeleterious to the recipient thereof. See, e.g., Remington, The Scienceand Practice of Pharmacy, 21st Edition; Lippincott Williams & Wilkins:Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 5thEdition; Rowe et al., ed., The Pharmaceutical Press and the AmericanPharmaceutical Association: 2005; and Handbook of PharmaceuticalAdditives, 3rd Edition; Ash and Ash ed., Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, Gibson ed., CRC PressLLC: Boca Raton, Fla., 2004.

As used herein, and unless otherwise specified, the term “hydrate” meansa compound provided herein or a salt thereof, which further includes astoichiometric or non-stoichiometric amount of water bound bynon-covalent intermolecular forces.

As used herein, and unless otherwise specified, the term “solvate” meansa solvate formed from the association of one or more solvent moleculesto a compound provided herein. The term “solvate” includes hydrates(e.g., mono-hydrate, dihydrate, trihydrate, tetrahydrate and the like).

As used herein, and unless otherwise specified, a compound describedherein is intended to encompass all possible stereoisomers, unless aparticular stereochemistry is specified. Where structural isomers of acompound are interconvertible via a low energy barrier, the compound mayexist as a single tautomer or a mixture of tautomers. This can take theform of proton tautomerism; or so-called valence tautomerism in thecompound, e.g., that contain an aromatic moiety.

As used herein, and unless otherwise specified, the term “contacting” isused in accordance with its plain ordinary meaning and refers to theprocess of allowing at least two distinct species (e.g. chemicalcompounds including biomolecules or cells) to become sufficientlyproximal to react, interact or physically touch. It should beappreciated; however, the resulting reaction product can be produceddirectly from a reaction between the added reagents or from anintermediate from one or more of the added reagents that can be producedin the reaction mixture. The term “contacting” may include allowing twospecies to react, interact, or physically touch, wherein the two speciesmay be a compound as described herein and a protein or enzyme. In someembodiments contacting includes allowing a compound described herein tointeract with a protein or enzyme that is involved in a signalingpathway.

As used herein, and unless otherwise specified, the term “modulation”,“modulate”, or “modulator” are used in accordance with their plainordinary meaning and refer to the act of changing or varying one or moreproperties. “Modulator” refers to a composition that increases ordecreases the level of a target molecule or the function of a targetmolecule or the physical state of the target of the molecule.“Modulation” refers to the process of changing or varying one or moreproperties. For example, as applied to the effects of a modulator on abiological target, to modulate means to change by increasing ordecreasing a property or function of the biological target or the amountof the biological target.

As used herein, and unless otherwise specified, the term “CCR4modulator” refers to a compound or a composition that increases ordecreases the level of CCR4 in a cell or a tissue, increases ordecreases the function of CCR4 or its physical state.

As defined herein, and unless otherwise specified, the term“activation”, “activate”, “activating” and the like in reference to atarget-inhibitor interaction means positively affecting (e.g.increasing) the activity or function of the target (e.g., protein)relative to the activity or function of the target (e.g., protein) inthe absence of the inhibitor. The terms reference activation, oractivating, sensitizing, or up-regulating signal transduction orenzymatic activity or the amount of a protein decreased in a disease.

As defined herein, and unless otherwise specified, the terms “agonist,”“activator,” “upregulator,” etc. refer to a substance capable ofdetectably increasing the expression or activity of a given gene orprotein relative to a control (e.g., in the absence of the agonist). Theagonist can increase expression or activity 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90% or more in comparison to a control in the absence ofthe agonist. In certain instances, expression or activity is 1.5-fold,2-fold, 3-fold, 4-fold, 5-fold, 10-fold or higher than the expression oractivity in the absence of the agonist. In embodiments, an agonist is amolecule that interacts with a target to cause or promote an increase inthe activation of the target. In embodiments, activators are moleculesthat increase, activate, facilitate, enhance activation, sensitize, orup-regulate, e.g., a gene, protein, ligand, receptor, or cell.

As defined herein, and unless otherwise specified, the term“inhibition,” “inhibit”, “inhibiting,” and the like, in reference to atarget-inhibitor interaction means negatively affecting (e.g.decreasing) the activity or function of the target (e.g., protein)relative to the activity or function of the target (e.g., protein) inthe absence of the inhibitor. In embodiments inhibition means negativelyaffecting (e.g. decreasing) the concentration or levels of the target(e.g., protein) relative to the concentration or level of the target(e.g., protein) in the absence of the inhibitor. In embodimentsinhibition refers to reduction of a disease or symptoms of disease. Inembodiments, inhibition refers to a reduction in the activity of aparticular protein target. Thus, inhibition includes, at least in part,partially or totally blocking stimulation, decreasing, preventing, ordelaying activation, or inactivating, desensitizing, or down-regulatingsignal transduction or enzymatic activity or the amount of a target(e.g., protein). In embodiments, inhibition refers to a reduction ofactivity of a target (e.g., protein) resulting from a direct interaction(e.g. an inhibitor binds to the target (e.g., protein)). In embodiments,inhibition refers to a reduction of activity of a target (e.g., protein)from an indirect interaction (e.g. an inhibitor binds to a protein thatactivates the target (e.g., protein), thereby preventing target (e.g.,protein) activation).

As defined herein, and unless otherwise specified, the terms“inhibitor,” “repressor” or “antagonist” or “downregulator”interchangeably refer to a substance capable of detectably decreasingthe expression or activity of a given gene or protein relative to acontrol (e.g., in the absence of the inhibitor). The antagonist candecrease expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%,90% or more in comparison to a control in the absence of the antagonist.In certain instances, expression or activity is 1.5-fold, 2-fold,3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activityin the absence of the antagonist. An antagonist prevents, reduces,inhibits, or neutralizes the activity of an agonist, and an antagonistcan also prevent, inhibit, or reduce constitutive activity of a target,e.g., a target receptor, even where there is no identified agonist. Inembodiments, inhibitors are molecules that decrease, block, prevent,delay activation, inactivate, desensitize, or down-regulate, e.g., agene, protein, ligand, receptor, or cell. An inhibitor may also bedefined as a molecule that reduces, blocks, or inactivates aconstitutive activity. An “antagonist” is a molecule that opposes theaction(s) of an agonist.

As defined herein, and unless otherwise specified, the term “expression”includes any step involved in the production of the polypeptideincluding, but not limited to, transcription, post-transcriptionalmodification, translation, post-translational modification, andsecretion. Expression can be detected using conventional techniques fordetecting protein (e.g., ELISA, Western blotting, flow cytometry,immunofluorescence, immunohistochemistry, etc.).

As defined herein, and unless otherwise specified, the terms “disease”or “condition” refer to a state of being or health status of a patientor subject capable of being treated with the compounds or methodsprovided herein. The disease may be a cancer. The disease may be anautoimmune disease. The disease may be an inflammatory disease. Thedisease may be an infectious disease. In some further instances,“cancer” refers to human cancers and carcinomas, sarcomas,adenocarcinomas, lymphomas, leukemias, etc., including solid andlymphoid cancers, kidney, breast, lung, bladder, colon, ovarian,prostate, pancreas, stomach, brain, head and neck, skin, uterine,testicular, glioma, esophagus, and liver cancer, includinghepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma,non-Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Celllymphomas), Hodgkin's lymphoma, leukemia (including MDS, AML, ALL, ATLLand CML), or multiple myeloma.

As defined herein, and unless otherwise specified, the term“inflammatory disease” refers to a disease or condition characterized byaberrant inflammation (e.g. an increased level of inflammation comparedto a control such as a healthy person not suffering from a disease).Examples of inflammatory diseases include autoimmune diseases,arthritis, rheumatoid arthritis, psoriatic arthritis, juvenileidiopathic arthritis, multiple sclerosis, systemic lupus erythematosus(SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitustype 1, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto'sthyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome,vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet'sdisease, Crohn's disease, ulcerative colitis, bullous pemphigoid,sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory boweldisease, Addison's disease, Vitiligo, asthma, allergic asthma, acnevulgaris, celiac disease, chronic prostatitis, pelvic inflammatorydisease, reperfusion injury, ischemia reperfusion injury, stroke,sarcoidosis, transplant rejection, interstitial cystitis,atherosclerosis, scleroderma, and atopic dermatitis. Such conditions arefrequently inextricably intertwined with other diseases, disorders andconditions. A non-limiting list of inflammatory-related diseases,disorders and conditions which may, for example, be caused byinflammatory cytokines, include, arthritis, kidney failure, lupus,asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, surgicalcomplications (e.g., where inflammatory cytokines prevent healing),anemia, and fibromyalgia. Other diseases and disorders which may beassociated with chronic inflammation include Alzheimer's disease,congestive heart failure, stroke, aortic valve stenosis,arteriosclerosis, osteoporosis, Parkinson's disease, infections,inflammatory bowel disease (IBD), allergic contact dermatitis and othereczemas, systemic sclerosis, transplantation and multiple sclerosis.Some of the aforementioned diseases, disorders and conditions for whicha compound (e.g., CCR4 inhibitor) described herein may be particularlyefficacious (due to, for example, limitations of current therapies) aredescribed in more detail hereafter. Examples of inflammatory diseasesinclude traumatic brain injury, arthritis, rheumatoid arthritis,psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis,systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onsetdiabetes, diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto'sencephalitis, Hashimoto's thyroiditis, ankylosing spondylitis,psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis,auto-immune thyroiditis, Behcet's disease, Crohn's disease, ulcerativecolitis, bullous pemphigoid, sarcoidosis, ichthyosis, Gravesophthalmopathy, inflammatory bowel disease, Addison's disease, Vitiligo,asthma, asthma, allergic asthma, acne vulgaris, celiac disease, chronicprostatitis, inflammatory bowel disease, pelvic inflammatory disease,reperfusion injury, sarcoidosis, transplant rejection, interstitialcystitis, atherosclerosis, and atopic dermatitis.

As defined herein, and unless otherwise specified, the term “cancer”refers to all types of cancer, neoplasm or malignant tumors found inmammals (e.g. humans), including leukemia, lymphoma, carcinomas andsarcomas. Exemplary cancers that may be treated with a compound ormethod provided herein include brain cancer, glioma, glioblastoma,neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer,cervical cancer, gastric cancer, ovarian cancer, lung cancer, and cancerof the head. Exemplary cancers that may be treated with a compound ormethod provided herein include cancer of the thyroid, endocrine system,brain, breast, cervix, colon, head & neck, liver, kidney, lung,non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach,uterus, Medulloblastoma, colorectal cancer, pancreatic cancer.Additional examples include, thyroid carcinoma, cholangiocarcinoma,pancreatic adenocarcinoma, skin cutaneous melanoma, colonadenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma,esophageal carcinoma, head and neck squamous cell carcinoma, breastinvasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma,Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma,neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer,rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia,primary brain tumors, cancer, malignant pancreatic insulinoma, malignantcarcinoid, urinary bladder cancer, premalignant skin lesions, testicularcancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer,genitourinary tract cancer, malignant hypercalcemia, endometrial cancer,adrenal cortical cancer, neoplasms of the endocrine or exocrinepancreas, medullary thyroid cancer, medullary thyroid carcinoma,melanoma, colorectal cancer, papillary thyroid cancer, hepatocellularcarcinoma, or prostate cancer.

As defined herein, and unless otherwise specified, the term “leukemia”refers broadly to progressive, malignant diseases of the blood-formingorgans and is generally characterized by a distorted proliferation anddevelopment of leukocytes and their precursors in the blood and bonemarrow. Leukemia is generally clinically classified on the basis of (1)the duration and character of the disease-acute or chronic; (2) the typeof cell involved; myeloid (myelogenous), lymphoid (lymphogenous), ormonocytic; and (3) the increase or non-increase in the number abnormalcells in the blood-leukemic or aleukemic (subleukemic). Exemplaryleukemias that may be treated with a compound or method provided hereininclude, for example, acute nonlymphocytic leukemia, chronic lymphocyticleukemia, acute granulocytic leukemia, chronic granulocytic leukemia,acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia,a leukocythemic leukemia, basophylic leukemia, blast cell leukemia,bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonalleukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia,hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia,stem cell leukemia, acute monocytic leukemia, leukopenic leukemia,lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia,lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia,mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia,monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloidgranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasmacell leukemia, multiple myeloma, plasmacytic leukemia, promyelocyticleukemia, Rieder cell leukemia, Schilling's leukemia, stem cellleukemia, subleukemic leukemia, or undifferentiated cell leukemia.

As defined herein, and unless otherwise specified, the term “lymphoma”refers to a group of cancers affecting hematopoietic and lymphoidtissues. It begins in lymphocytes, the blood cells that are foundprimarily in lymph nodes, spleen, thymus, and bone marrow. Two maintypes of lymphoma are non-Hodgkin lymphoma and Hodgkin's disease.Hodgkin's disease represents approximately 15% of all diagnosedlymphomas. This is a cancer associated with Reed-Sternberg malignant Blymphocytes. Non-Hodgkin's lymphomas (NHL) can be classified based onthe rate at which cancer grows and the type of cells involved. There areaggressive (high grade) and indolent (low grade) types of NHL. Based onthe type of cells involved, there are B-cell and T-cell NHLs. ExemplaryB-cell lymphomas that may be treated with a compound or method providedherein include, but are not limited to, small lymphocytic lymphoma,Mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma,extranodal (MALT) lymphoma, nodal (monocytoid B-cell) lymphoma, spleniclymphoma, diffuse large cell B-lymphoma, Burkitt's lymphoma,lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursorB-lymphoblastic lymphoma. Exemplary T-cell lymphomas that may be treatedwith a compound or method provided herein include, but are not limitedto, cunateous T-cell lymphoma, peripheral T-cell lymphoma, anaplasticlarge cell lymphoma, mycosis fungoides, and precursor T-lymphoblasticlymphoma.

As defined herein, and unless otherwise specified, the term “sarcoma”generally refers to a tumor which is made up of a substance like theembryonic connective tissue and is generally composed of closely packedcells embedded in a fibrillar or homogeneous substance. Sarcomas thatmay be treated with a compound or method provided herein include achondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma,osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolarsoft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloromasarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma,endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma,fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma,Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma,immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma ofT-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma,angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parostealsarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma,synovial sarcoma, or telangiectaltic sarcoma.

As defined herein, and unless otherwise specified, the term “melanoma”is taken to mean a tumor arising from the melanocytic system of the skinand other organs. Melanomas that may be treated with a compound ormethod provided herein include, for example, acral-lentiginous melanoma,amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo malignamelanoma, malignant melanoma, nodular melanoma, subungal melanoma, orsuperficial spreading melanoma.

As defined herein, and unless otherwise specified, the term “carcinoma”refers to a malignant new growth made up of epithelial cells tending toinfiltrate the surrounding tissues and give rise to metastases.Exemplary carcinomas that may be treated with a compound or methodprovided herein include, for example, thyroid carcinoma,cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma,colon adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma,esophageal carcinoma, head and neck squamous cell carcinoma, breastinvasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma,medullary thyroid carcinoma, familial medullary thyroid carcinoma,acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoidcystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex,alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma,carcinoma basocellulare, basaloid carcinoma, basosquamous cellcarcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma,bronchogenic carcinoma, cerebriform carcinoma, cholangiocellularcarcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma,corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinomacutaneum, cylindrical carcinoma, cylindrical cell carcinoma, ductcarcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma,epiermoid carcinoma, carcinoma epitheliale adenoides, exophyticcarcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatinifornicarcinoma, gelatinous carcinoma, giant cell carcinoma, carcinomagigantocellulare, glandular carcinoma, granulosa cell carcinoma,hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma,Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma,infantile embryonal carcinoma, carcinoma in situ, intraepidermalcarcinoma, intraepithelial carcinoma, Krompecher's carcinoma,Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma,carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma,carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinomamolle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare,mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinomamyxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinomaossificans, osteoid carcinoma, papillary carcinoma, periportalcarcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceouscarcinoma, renal cell carcinoma of kidney, reserve cell carcinoma,carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma,carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex,small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma,spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma,squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum,carcinoma telangiectodes, transitional cell carcinoma, carcinomatuberosum, tuberous carcinoma, verrucous carcinoma, or carcinomavillosum.

As defined herein, and unless otherwise specified, the term “autoimmunedisease” refers to a disease or condition in which a subject's immunesystem has an aberrant immune response against a substance that does notnormally elicit an immune response in a healthy subject. Examples ofautoimmune diseases that may be treated with a compound, pharmaceuticalcomposition, or method described herein include Acute DisseminatedEncephalomyelitis (ADEM), Acute necrotizing hemorrhagicleukoencephalitis, Addison's disease, Agammaglobulinemia, Alopeciaareata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBMnephritis, Antiphospholipid syndrome (APS), Autoimmune angioedema,Autoimmune aplastic anemia, Autoimmune dysautonomia, Autoimmunehepatitis, Autoimmune hyperlipidemia, Autoimmune immunodeficiency,Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmuneoophoritis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmunethrombocytopenic purpura (ATP), Autoimmune thyroid disease, Autoimmuneurticaria, Axonal or neuronal neuropathies, Balo disease, Behcet'sdisease, Bullous pemphigoid, Cardiomyopathy, Castleman disease, Celiacdisease, Chagas disease, Chronic fatigue syndrome, Chronic inflammatorydemyelinating polyneuropathy (CIDP), Chronic recurrent multifocalostomyelitis (CRMO), Churg-Strauss syndrome, Cicatricialpemphigoid/benign mucosal pemphigoid, Crohn's disease, Cogans syndrome,Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis,CREST disease, Essential mixed cryoglobulinemia, Demyelinatingneuropathies, Dermatitis herpetiformis, Dermatomyositis, Devic's disease(neuromyelitis optica), Discoid lupus, Dressler's syndrome,Endometriosis, Eosinophilic esophagitis, Eosinophilic fasciitis,Erythema nodosum, Experimental allergic encephalomyelitis, Evanssyndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis(temporal arteritis), Giant cell myocarditis, Glomerulonephritis,Goodpasture's syndrome, Granulomatosis with Polyangiitis (GPA) (formerlycalled Wegener's Granulomatosis), Graves' disease, Guillain-Barresyndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, Hemolyticanemia, Henoch-Schonlein purpura, Herpes gestationis,Hypogammaglobulinemia, Idiopathic thrombocytopenic purpura (ITP), IgAnephropathy, IgG4-related sclerosing disease, Immunoregulatorylipoproteins, Inclusion body myositis, Interstitial cystitis, Juvenilearthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis,Kawasaki syndrome, Lambert-Eaton syndrome, Leukocytoclastic vasculitis,Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgAdisease (LAD), Lupus (SLE), Lyme disease, chronic, Meniere's disease,Microscopic polyangiitis, Mixed connective tissue disease (MCTD),Mooren's ulcer, Mucha-Habermann disease, Multiple sclerosis, Myastheniagravis, Myositis, Narcolepsy, Neuromyelitis optica (Devic's),Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromicrheumatism, PANDAS (Pediatric Autoimmune Neuropsychiatric DisordersAssociated with Streptococcus), Paraneoplastic cerebellar degeneration,Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome,Parsonnage-Turner syndrome, Pars planitis (peripheral uveitis),Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis,Pernicious anemia, POEMS syndrome, Polyarteritis nodosa, Type I, II, &III autoimmune polyglandular syndromes, Polymyalgia rheumatica,Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomysyndrome, Progesterone dermatitis, Primary biliary cirrhosis, Primarysclerosing cholangitis, Psoriasis, Psoriatic arthritis, Idiopathicpulmonary fibrosis, Pyoderma gangrenosum, Pure red cell aplasia,Raynauds phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy,Reiter's syndrome, Relapsing polychondritis, Restless legs syndrome,Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis,Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren'ssyndrome, Sperm & testicular autoimmunity, Stiff person syndrome,Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympatheticophthalmia, Takayasu's arteritis, Temporal arteritis/Giant cellarteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome,Transverse myelitis, Type 1 diabetes, Ulcerative colitis,Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis,Vesiculobullous dermatosis, Vitiligo, or Wegener's granulomatosis (i.e.,Granulomatosis with Polyangiitis (GPA).

As defined herein, and unless otherwise specified, the terms “treating”or “treatment” refer to any indicia of success in the therapy oramelioration of an injury, disease, pathology or condition, includingany objective or subjective parameter such as abatement; remission;diminishing of symptoms or making the injury, pathology or conditionmore tolerable to the patient; slowing in the rate of degeneration ordecline; making the final point of degeneration less debilitating;improving a patient's physical or mental well-being. The treatment oramelioration of symptoms can be based on objective or subjectiveparameters; including the results of a physical examination,neuropsychiatric exams, and/or a psychiatric evaluation. The term“treating” and conjugations thereof, may include prevention of aninjury, pathology, condition, or disease. In embodiments, treating ispreventing. In embodiments, treating does not include preventing. Inembodiments, the treating or treatment is no prophylactic treatment.

“Treating” or “treatment” as used herein (and as well-understood in theart) also broadly includes any approach for obtaining beneficial ordesired results in a subject's condition, including clinical results.Beneficial or desired clinical results can include, but are not limitedto, alleviation or amelioration of one or more symptoms or conditions,diminishment of the extent of a disease, stabilizing (i.e., notworsening) the state of disease, prevention of a disease's transmissionor spread, delay or slowing of disease progression, amelioration orpalliation of the disease state, diminishment of the reoccurrence ofdisease, and remission, whether partial or total and whether detectableor undetectable. In other words, “treatment” as used herein includes anycure, amelioration, or prevention of a disease. Treatment may preventthe disease from occurring; inhibit the disease's spread; relieve thedisease's symptoms (e.g., ocular pain, seeing halos around lights, redeye, very high intraocular pressure), fully or partially remove thedisease's underlying cause, shorten a disease's duration, or do acombination of these things.

“Treating” and “treatment” as used herein include prophylactictreatment. Treatment methods include administering to a subject atherapeutically effective amount of a compound described herein. Theadministering step may consist of a single administration or may includea series of administrations. The length of the treatment period dependson a variety of factors, such as the severity of the condition, the ageof the patient, the concentration of the compound, the activity of thecompositions used in the treatment, or a combination thereof. It willalso be appreciated that the effective dosage of an agent used for thetreatment or prophylaxis may increase or decrease over the course of aparticular treatment or prophylaxis regime. Changes in dosage may resultand become apparent by standard diagnostic assays known in the art. Insome instances, chronic administration may be required. For example, thecompositions are administered to the subject in an amount and for aduration sufficient to treat the patient.

As defined herein, and unless otherwise specified, the term “prevent”refers to a decrease in the occurrence of disease symptoms in a patient.As indicated above, the prevention may be complete (no detectablesymptoms) or partial, such that fewer symptoms are observed than wouldlikely occur absent treatment. In embodiments, prevent refers to slowingthe progression of the disease, disorder or condition or inhibitingprogression thereof to a harmful or otherwise undesired state.

As defined herein, and unless otherwise specified, the term “Patient” or“subject in need thereof” refers to a living organism suffering from orprone to a disease or condition that can be treated by administration ofa pharmaceutical composition as provided herein. Non-limiting examplesinclude humans, other mammals, bovines, rats, mice, dogs, monkeys, goat,sheep, cows, deer, and other non-mammalian animals. In some embodiments,a patient is human.

As defined herein, and unless otherwise specified, an “effective amount”is an amount sufficient for a compound to accomplish a stated purposerelative to the absence of the compound (e.g. achieve the effect forwhich it is administered, treat a disease, reduce enzyme activity,increase enzyme activity, reduce a signaling pathway, or reduce one ormore symptoms of a disease or condition). An example of an “effectiveamount” is an amount sufficient to contribute to the treatment,prevention, or reduction of a symptom or symptoms of a disease, whichcould also be referred to as a “therapeutically effective amount.” A“reduction” of a symptom or symptoms (and grammatical equivalents ofthis phrase) means decreasing of the severity or frequency of thesymptom(s), or elimination of the symptom(s). A “prophylacticallyeffective amount” of a drug is an amount of a drug that, whenadministered to a subject, will have the intended prophylactic effect,e.g., preventing or delaying the onset (or reoccurrence) of an injury,disease, pathology or condition, or reducing the likelihood of the onset(or reoccurrence) of an injury, disease, pathology, or condition, ortheir symptoms. The full prophylactic effect does not necessarily occurby administration of one dose, and may occur only after administrationof a series of doses. Thus, a prophylactically effective amount may beadministered in one or more administrations. An “activity decreasingamount,” as used herein, refers to an amount of antagonist required todecrease the activity of an enzyme relative to the absence of theantagonist. A “function disrupting amount,” as used herein, refers tothe amount of antagonist required to disrupt the function of an enzymeor protein relative to the absence of the antagonist. The exact amountswill depend on the purpose of the treatment, and will be ascertainableby one skilled in the art using known techniques (see, e.g., Lieberman,Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Scienceand Technology of Pharmaceutical Compounding (1999); Pickar, DosageCalculations (1999); and Remington: The Science and Practice ofPharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams &Wilkins). The therapeutically effective amount can be ascertained bymeasuring relevant physiological effects, and it can be adjusted inconnection with the dosing regimen and diagnostic analysis of thesubject's condition, and the like. By way of example, measurement of theserum level of a CCR4 inhibitor (or, e.g., a metabolite thereof) at aparticular time post-administration may be indicative of whether atherapeutically effective amount has been administered.

For any compound described herein, the therapeutically effective amountcan be initially determined from cell culture assays. Targetconcentrations will be those concentrations of active compound(s) thatare capable of achieving the methods described herein, as measured usingthe methods described herein or known in the art.

As is well known in the art, therapeutically effective amounts for usein humans can also be determined from animal models. For example, a dosefor humans can be formulated to achieve a concentration that has beenfound to be effective in animals. The dosage in humans can be adjustedby monitoring compounds effectiveness and adjusting the dosage upwardsor downwards, as described above. Adjusting the dose to achieve maximalefficacy in humans based on the methods described above and othermethods is well within the capabilities of the ordinarily skilledartisan. Adjusting the dose to achieve maximal therapeutic windowefficacy or toxicity in humans based on the methods described above andother methods is well within the capabilities of the ordinarily skilledartisan.

As defined herein, and unless otherwise specified, the term“therapeutically effective amount,” as used herein, refers to thatamount of the therapeutic agent sufficient to ameliorate the disorder,as described above. For example, for the given parameter, atherapeutically effective amount will show an increase or decrease of atleast 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least100%. Therapeutic efficacy can also be expressed as “-fold”increase ordecrease. For example, a therapeutically effective amount can have atleast a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over acontrol.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present invention should be sufficient to effect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side-effects. Determination of the proper dosage for aparticular situation is within the skill of the practitioner. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached. Dosage amounts and intervals can be adjusted individually toprovide levels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

As defined herein, and unless otherwise specified, the term“administering” means oral administration, administration as asuppository, topical contact, intravenous, parenteral, intraperitoneal,intramuscular, intralesional, intrathecal, intracranial, intranasal orsubcutaneous administration, or the implantation of a slow-releasedevice, e.g., a mini-osmotic pump, to a subject. Administration is byany route, including parenteral and transmucosal (e.g., buccal,sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal).Parenteral administration includes, e.g., intravenous, intramuscular,intra-arteriole, intradermal, subcutaneous, intraperitoneal,intraventricular, and intracranial. Other modes of delivery include, butare not limited to, the use of liposomal formulations, intravenousinfusion, transdermal patches, etc. By “co-administer” it is meant thata composition described herein is administered at the same time, justprior to, or just after the administration of one or more additionaltherapies (e.g. anti-cancer agent, chemotherapeutic, or treatment for aneurodegenerative disease). In embodiments, the administering does notinclude administration of any active agent other than the recited activeagent. The compound of the invention can be administered alone or can becoadministered to the patient. Coadministration is meant to includesimultaneous or sequential administration of the compound individuallyor in combination (more than one compound or agent). Thus, thepreparations can also be combined, when desired, with other activesubstances (e.g. to reduce metabolic degradation). The compositions ofthe present invention can be delivered by transdermally, by a topicalroute, formulated as applicator sticks, solutions, suspensions,emulsions, gels, creams, ointments, pastes, jellies, paints, powders,and aerosols. Oral preparations include tablets, pills, powder, dragees,capsules, liquids, lozenges, cachets, gels, syrups, slurries,suspensions, etc., suitable for ingestion by the patient. Solid formpreparations include powders, tablets, pills, capsules, cachets,suppositories, and dispersible granules. Liquid form preparationsinclude solutions, suspensions, and emulsions, for example, water orwater/propylene glycol solutions. The compositions of the presentinvention may additionally include components to provide sustainedrelease and/or comfort. Such components include high molecular weight,anionic mucomimetic polymers, gelling polysaccharides and finely-divideddrug carrier substrates. These components are discussed in greaterdetail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760.The entire contents of these patents are incorporated herein byreference in their entirety for all purposes. The compositions of thepresent invention can also be delivered as microspheres for slow releasein the body. For example, microspheres can be administered viaintradermal injection of drug-containing microspheres, which slowlyrelease subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645,1995; as biodegradable and injectable gel formulations (see, e.g., GaoPharm. Res. 12:857-863, 1995); or, as microspheres for oraladministration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674,1997). In another embodiment, the formulations of the compositions ofthe present invention can be delivered by the use of liposomes whichfuse with the cellular membrane or are endocytosed, i.e., by employingreceptor ligands attached to the liposome, that bind to surface membraneprotein receptors of the cell resulting in endocytosis. By usingliposomes, particularly where the liposome surface carries receptorligands specific for target cells, or are otherwise preferentiallydirected to a specific organ, one can focus the delivery of thecompositions of the present invention into the target cells in vivo.(See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn,Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm.46:1576-1587, 1989). The compositions of the present invention can alsobe delivered as nanoparticles. In embodiments, the administering doesnot include administration of any active agent other than the recitedactive agent.

As defined herein, and unless otherwise specified, “co-administer” meansthat a composition described herein is administered at the same time,just prior to, or just after the administration of one or moreadditional therapies. The compounds of the invention can be administeredalone or can be coadministered to the patient. Coadministration is meantto include simultaneous or sequential administration of the compoundsindividually or in combination (more than one compound). Thecompositions of the present invention can be delivered transdermally, bya topical route, or formulated as applicator sticks, solutions,suspensions, emulsions, gels, creams, ointments, pastes, jellies,paints, powders, and aerosols.

For any compound described herein, the therapeutically effective amountcan be initially determined from cell culture assays. Targetconcentrations will be those concentrations of active compound(s) thatare capable of achieving the methods described herein, as measured usingthe methods described herein or known in the art.

As is well known in the art, therapeutically effective amounts for usein humans can also be determined from animal models. For example, a dosefor humans can be formulated to achieve a concentration that has beenfound to be effective in animals. The dosage in humans can be adjustedby monitoring compounds effectiveness and adjusting the dosage upwardsor downwards, as described above. Adjusting the dose to achieve maximalefficacy in humans based on the methods described above and othermethods is well within the capabilities of the ordinarily skilledartisan.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present invention should be sufficient to affect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side-effects. Determination of the proper dosage for aparticular situation is within the skill of the practitioner. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached.

Dosage amounts and intervals can be adjusted individually to providelevels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

Utilizing the teachings provided herein, an effective prophylactic ortherapeutic treatment regimen can be planned that does not causesubstantial toxicity and yet is effective to treat the clinical symptomsdemonstrated by the particular patient. This planning should involve thecareful choice of active compound by considering factors such ascompound potency, relative bioavailability, patient body weight,presence and severity of adverse side effects, preferred mode ofadministration and the toxicity profile of the selected agent.

The compounds described herein can be used in combination with oneanother, with other active agents known to be useful in treating cancer(e.g. colon cancer), cardiovascular disease, metabolic disease, immuneor inflammatory disease or disorder.

In some embodiments, co-administration includes administering one activeagent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, 2 days, 4days, 1 week or 1 month of a second active agent. Co-administrationincludes administering two active agents simultaneously, approximatelysimultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes ofeach other), or sequentially in any order. In some embodiments,co-administration can be accomplished by co-formulation, i.e., preparinga single pharmaceutical composition including both active agents. Inother embodiments, the active agents can be formulated separately. Inanother embodiment, the active and/or adjunctive agents may be linked orconjugated to one another. In some embodiments, the compounds describedherein may be combined with treatments for cancer (e.g. colon cancer),cardiovascular disease, metabolic disease, immune or inflammatorydisease or disorder.

As defined herein, and unless otherwise specified, “Cardiovascularagent” is used in accordance with its plain ordinary meaning and refersto a composition (e.g. compound, drug, antagonist, inhibitor, modulator)used in any way to treat conditions of the heart or the circulatory orvascular system relative to a control. In some embodiments, acardiovascular agent is an agent identified herein having utility inmethods of treating cardiovascular disease or disorder. In someembodiments, a cardiovascular agent is an agent approved by the FDA orsimilar regulatory agency of a country other than the USA, for treatingcardiovascular disease or disorder.

As defined herein, and unless otherwise specified, [0001]“anti-inflammatory agent” is used in accordance with its plain ordinarymeaning and refers to a composition (e.g. compound, drug, antagonist,inhibitor, modulator) used in any way to reduce inflammation or swellingrelative to a control (e.g., the absence of the agent). In someembodiments, an anti-inflammatory agent is an agent identified hereinhaving utility in methods of treating an inflammatory disease ordisorder. In some embodiments, an anti-inflammatory agent is an agentapproved by the FDA or similar regulatory agency of a country other thanthe USA, for reducing swelling and inflammation.

The compounds described herein can be administered to treat an immune orinflammatory disease or disorder, a cardiovascular or metabolic diseaseor disorder and/or cancer. In this regard, the compounds disclosedherein may be administered either alone to treat such diseases ordisorders or may be co-administered with another therapeutic agent totreat such diseases or disorders.

The compounds disclosed herein may be co-administered with a cytokine oragonist or antagonist of cytokine function, (including agents which acton cytokine signaling pathways such as modulators of the SOCS system)including alpha-, beta-, and gamma-interferons; insulin-like growthfactor type I (IGF-1); interleukins (IL) including IL1 to 17, andinterleukin antagonists or inhibitors such as analcinra; tumour necrosisfactor alpha (TNF-.alpha.) inhibitors such as anti-TNF monoclonalantibodies (for example infliximab; adalimumab, and CDP-870) and TNFreceptor antagonists including immunoglobulin molecules (such asetanercept) and low-molecular-weight agents such as pentoxifylline.

The compounds disclosed herein may be co-administered with ananti-inflammatory agent, such as thalidomide or a derivative thereof, aretinoid, dithranol or calcipotriol, a non-steroidal anti-inflammatoryagent (hereinafter NSAID) including non-selective cyclo-oxygenaseCOX-1/COX-2 inhibitors whether applied topically or systemically (suchas piroxicam, diclofenac, propionic acids such as naproxen,flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such asmefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones suchas phenylbutazone, salicylates such as aspirin); selective COX-2inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib,lumarocoxib, parecoxib and etoricoxib); cyclo-oxygenase inhibitingnitric oxide donors (CINODs); glucocorticosteroids (whether administeredby topical, oral, intramuscular, intravenous, or intra-articularroutes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine;auranofin or other parenteral or oral gold preparations; analgesics;diacerein; intra-articular therapies such as hyaluronic acidderivatives; and nutritional supplements such as glucosamine.

The compounds disclosed herein may be co-administered with a calciumchannel blocker, a beta-adrenoceptor blocker, an angiotensin-convertingenzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipidlowering agent such as a statin or a fibrate; a modulator of blood cellmorphology such as pentoxifylline; thrombolytic, or an anticoagulantsuch as a platelet aggregation inhibitor.

As defined herein, and unless otherwise specified, “Anti-cancer agent”and “anticancer agent” are used in accordance with their plain ordinarymeaning and refers to a composition (e.g. compound, drug, antagonist,inhibitor, modulator) having antineoplastic properties or the ability toinhibit the growth or proliferation of cells. In some embodiments, ananti-cancer agent is a chemotherapeutic. In some embodiments, ananti-cancer agent is an agent identified herein having utility inmethods of treating cancer. In some embodiments, an anti-cancer agent isan agent approved by the FDA or similar regulatory agency of a countryother than the USA, for treating cancer. Examples of anti-cancer agentsinclude, but are not limited to, MEK (e.g. MEK1, MEK2, or MEK1 and MEK2)inhibitors (e.g. XL518, CI-1040, PD035901, selumetinib/AZD6244,GSK1120212/trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901,U0126, PD98059, TAK-733, PD318088, AS703026, BAY 869766), alkylatingagents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan,melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogenmustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil,meiphalan), ethylenimine and methylmelamines (e.g., hexamethlymelamine,thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g.,carmustine, lomusitne, semustine, streptozocin), triazenes(decarbazine)), anti-metabolites (e.g., 5-azathioprine, leucovorin,capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folicacid analog (e.g., methotrexate), or pyrimidine analogs (e.g.,fluorouracil, floxouridine, Cytarabine), purine analogs (e.g.,mercaptopurine, thioguanine, pentostatin), etc.), plant alkaloids (e.g.,vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin,paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g.,irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate,teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin,daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin,mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g.cisplatin, oxaloplatin, carboplatin), anthracenedione (e.g.,mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazinederivative (e.g., procarbazine), adrenocortical suppressant (e.g.,mitotane, aminoglutethimide), epipodophyllotoxins (e.g., etoposide),antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g.,L-asparaginase), inhibitors of mitogen-activated protein kinasesignaling (e.g. U0126, PD98059, PD184352, PD0325901, ARRY-142886,SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002, Sykinhibitors, mTOR inhibitors, antibodies (e.g., rituxan), gossyphol,genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA),bryostatin, tumor necrosis factor-related apoptosis-inducing ligand(TRAIL), 5-aza-2′-deoxycytidine, all trans retinoic acid, doxorubicin,vincristine, etoposide, gemcitabine, imatinib (Gleevec®), geldanamycin,17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol,LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, PD184352,20-epi-1, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TKantagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen,prostatic carcinoma; antiestrogen; antineoplaston; antisenseoligonucleotides; aphidicolin glycinate; apoptosis gene modulators;apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; argininedeaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatinIII derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistrateneA; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2;capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRestM3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinaseinhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;clomifene analogues; clotrimazole; collismycin A; collismycin B;combretastatin A4; combretastatin analogue; conagenin; crambescidin 816;crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemnin B; didox; diethylnorspermine;dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol;dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA;ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene;emitefur; epirubicin; epristeride; estramustine analogue; estrogenagonists; estrogen antagonists; etanidazole; etoposide phosphate;exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin;pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenyl acetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen-binding protein; sizofuran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatinstimalamer, Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin,acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin;aldesleukin; altretamine; ambomycin; ametantrone acetate;aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase;asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa;bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin;bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol;chlorambucil; cirolemycin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride;decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate;diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene;droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate;eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate;epipropidine; epirubicin hydrochloride; erbulozole; esorubicinhydrochloride; estramustine; estramustine phosphate sodium; etanidazole;etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride;fazarabine; fenretinide; floxuridine; fludarabine phosphate;fluorouracil; fluorocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; iimofosine; interleukin (includingrecombinant interleukin II, or rlL.sub.2), interferon alfa-2a;interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferonbeta-1a; interferon gamma-1b; iproplatin; irinotecan hydrochloride;lanreotide acetate; letrozole; leuprolide acetate; liarozolehydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride;masoprocol; maytansine; mechlorethamine hydrochloride; megestrolacetate; melengestrol acetate; melphalan; menogaril; mercaptopurine;methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide;mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper;mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole;nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin;pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan;piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium;porfiromycin; prednimustine; procarbazine hydrochloride; puromycin;puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol;safingol hydrochloride; semustine; simtrazene; sparfosate sodium;sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin;streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium;tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicinhydrochloride, agents that arrest cells in the G2-M phases and/ormodulate the formation or stability of microtubules, (e.g. Taxol™ (i.e.paclitaxel), Taxotere™, compounds comprising the taxane skeleton,Erbulozole (i.e. R-55104), Dolastatin 10 (i.e. DLS-10 and NSC-376128),Mivobulin isethionate (i.e. as CI-980), Vincristine, NSC-639829,Discodermolide (i.e. as NVP-XX-A-296), ABT-751 (Abbott, i.e. E-7010),Altorhyrtins (e.g. Altorhyrtin A and Altorhyrtin C), Spongistatins (e.g.Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4,Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, andSpongistatin 9), Cemadotin hydrochloride (i.e. LU-103793 andNSC-D-669356), Epothilones (e.g. Epothilone A, Epothilone B, EpothiloneC (i.e. desoxyepothilone A or dEpoA), Epothilone D (i.e. KOS-862, dEpoB,and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone BN-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B(i.e. BMS-310705), 21-hydroxyepothilone D (i.e. Desoxyepothilone F anddEpoF), 26-fluoroepothilone, Auristatin PE (i.e. NSC-654663), Soblidotin(i.e. TZT-1027), LS-4559-P (Pharmacia, i.e. LS-4577), LS-4578(Pharmacia, i.e. LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia),RPR-112378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877(Fujisawa, i.e. WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2(Hungarian Academy of Sciences), BSF-223651 (BASF, i.e. ILX-651 andLU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis),AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko),IDN-5005 (Indena), Cryptophycin 52 (i.e. LY-355703), AC-7739 (Ajinomoto,i.e. AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, i.e. AVE-8062,AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide, TubulysinA, Canadensol, Centaureidin (i.e. NSC-106969), T-138067 (Tularik, i.e.T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute, i.e.DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas StateUniversity), Oncocidin A1 (i.e. BTO-956 and DIME), DDE-313 (ParkerHughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker HughesInstitute), SPA-1 (Parker Hughes Institute, i.e. SPIKET-P), 3-IAABU(Cytoskeleton/Mt. Sinai School of Medicine, i.e. MF-569), Narcosine(also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972(Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School ofMedicine, i.e. MF-191), TMPN (Arizona State University), Vanadoceneacetylacetonate, T-138026 (Tularik), Monsatrol, lnanocine (i.e.NSC-698666), 3-IAABE (Cytoskeleton/Mt. Sinai School of Medicine),A-204197 (Abbott), T-607 (Tuiarik, i.e. T-900607), RPR-115781 (Aventis),Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin,lsoeleutherobin A, and Z-Eleutherobin), Caribaeoside, Caribaeolin,Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica),Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A,TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (−)-Phenylahistin(i.e. NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica),Myoseverin B, D-43411 (Zentaris, i.e. D-81862), A-289099 (Abbott),A-318315 (Abbott), HTI-286 (i.e. SPA-110, trifluoroacetate salt)(Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI),Resverastatin phosphate sodium, BPR-OY-007 (National Health ResearchInstitutes), and SSR-250411 (Sanofi)), steroids (e.g., dexamethasone),finasteride, aromatase inhibitors, gonadotropin-releasing hormoneagonists (GnRH) such as goserelin or leuprolide, adrenocorticosteroids(e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate,megestrol acetate, medroxyprogesterone acetate), estrogens (e.g.,diethylstilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen),androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen(e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guérin(BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonalantibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, andanti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonalantibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy(e.g., anti-CD20 monoclonal antibody conjugated to ¹¹¹In, ⁹⁰Y, or ¹³¹I,etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin,epirubicin, topotecan, itraconazole, vindesine, cerivastatin,vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan,clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib,gefitinib, EGFR inhibitors, epidermal growth factor receptor(EGFR)-targeted therapy or therapeutic (e.g. gefitinib (Iressa™)erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™),panitumumab (Vectibix™) vandetanib (Caprelsa™), afatinib/BIBW2992,CI-1033/canertinib, neratinib/HKI-272, CP-724714, TAK-285, AST-1306,ARRY334543, ARRY-380, AG-1478, dacomitinib/PF299804, OSI-420/desmethylerlotinib, AZD8931, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002,WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib,sunitinib, dasatinib, or the like.

“Chemotherapeutic” or “chemotherapeutic agent” is used in accordancewith its plain ordinary meaning and refers to a chemical composition orcompound having antineoplastic properties or the ability to inhibit thegrowth or proliferation of cells.

Additionally, the compounds described herein can be co-administered withconventional immunotherapeutic agents including, but not limited to,immunostimulants (e.g., Bacillus Calmette-Guérin (BCG), levamisole,interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g.,anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonalantibodies), immunotoxins (e.g., anti-CD33 monoclonalantibody-calicheamicin conjugate, anti-CD22 monoclonalantibody-pseudomonas exotoxin conjugate, etc.), and radioimmunotherapy(e.g., anti-CD20 monoclonal antibody conjugated to ¹¹¹In, ⁹⁰Y, or ¹³¹I,etc.).

The compounds disclosed herein may be co-administered with anantiproliferative/antineoplastic drug or a combination thereof, as usedin medical oncology, such as an alkylating agent (for examplecis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan,chlorambucil, busulphan or a nitrosourea); an antimetabolite (forexample an antifolate such as a fluoropyrimidine like 5-fluorouracil ortegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea,gemcitabine or paclitaxel); an antitumour antibiotic (for example ananthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin,epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); anantimitotic agent (for example a vinca alkaloid such as vincristine,vinblastine, vindesine or vinorelbine, or a taxoid such as taxol ortaxotere); or a topoisomerase inhibitor (for example anepipodophyllotoxin such as etoposide, teniposide, amsacrine, topotecanor a camptothecin); (ii) a cytostatic agent such as an antioestrogen(for example tamoxifen, toremifene, raloxifene, droloxifene oriodoxyfene), an oestrogen receptor down regulator (for examplefulvestrant), an antiandrogen (for example bicalutamide, flutamide,nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist(for example goserelin, leuprorelin or buserelin), a progestogen (forexample megestrol acetate), an aromatase inhibitor (for example asanastrozole, letrozole, vorazole or exemestane) or an inhibitor of5α-reductase such as finasteride; (iii) an agent which inhibits cancercell invasion (for example a metalloproteinase inhibitor like marimastator an inhibitor of urokinase plasminogen activator receptor function);(iv) an inhibitor of growth factor function, for example: a growthfactor antibody (for example the anti-erbb2 antibody trastuzumab, or theanti-erbb1 antibody cetuximab [C225]), a farnesyl transferase inhibitor,a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, aninhibitor of the epidermal growth factor family (for example an EGFRfamily tyrosine kinase inhibitor such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoli-n-4-amine(gefitinib, AZD 1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) or6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazoli-n-4-amine(CI 1033)), an inhibitor of the platelet-derived growth factor family,or an inhibitor of the hepatocyte growth factor family; (v) anantiangiogenic agent such as one which inhibits the effects of vascularendothelial growth factor (for example the anti-vascular endothelialcell growth factor antibody bevacizumab, a compound disclosed in WO97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound thatworks by another mechanism (for example linomide, an inhibitor ofintegrin .alpha.v.beta.3 function or an angiostatin); (vi) a vasculardamaging agent such as combretastatin A4, or a compound disclosed in WO99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO02/08213; (vii) an agent used in anti sense therapy, for example onedirected to one of the targets listed above, such as ISIS 2503, ananti-ras antisense; (viii) an agent used in a gene therapy approach, forexample approaches to replace aberrant genes such as aberrant p53 oraberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy)approaches such as those using cytosine deaminase, thymidine kinase or abacterial nitroreductase enzyme and approaches to increase patienttolerance to chemotherapy or radiotherapy such as multi-drug resistancegene therapy; or (ix) an agent used in an immunotherapeutic approach,for example ex-vivo and in-vivo approaches to increase theimmunogenicity of patient tumour cells, such as transfection withcytokines such as interleukin 2, interleukin 4 or granulocyte-macrophagecolony stimulating factor, approaches to decrease T-cell anergy,approaches using transfected immune cells such as cytokine-transfecteddendritic cells, approaches using cytokine-transfected tumour cell linesand approaches using anti-idiotypic antibodies.

VI. CCR4 MODULATORS

Any known CCR4 modulator can be used in performing the presentlydisclosed treatment methods. In certain embodiments, the CCR4 modulatoris one that is suitable for oral administration. In other embodiments,the CCR4 modulator is one that is suitable for parental administration.In other embodiments, the CCR4 modulator is a CCR4-binding antibody.

Orally-Administered CCR4 Modulators

Provided are compounds useful for the treatment of EPV+ malignancies.One group of CCR4 modulators are compounds disclosed in U.S. patentapplication Ser. No. 15/662,861 filed Jul. 28, 2017 of Beck et al.(e.g., for example, compounds of Formulae I through VII), which areincorporated herein by reference in its entirety for all purposes. Inembodiments, the compounds having Formula I:

or a pharmaceutically acceptable salt thereof,wherein:

-   -   X¹ is CR⁸ or N;    -   X² is CR⁹ or N;    -   X³ is CR¹⁰ or N;    -   n1, n2, n3, n4, n5, n6, n7, n8, n9 and n10 are independently an        integer from 0 to 4;    -   m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, v1, v2, v3, v4, v5, v6,        v7, v8, v9 and v10 are independently 1 or 2;    -   z1 is an integer from 0 to 5;    -   z2 is an integer from 0 to 2;    -   z3 is an integer from 0 to 11;    -   z4 is an integer from 0 to 2;    -   L⁷ is a bond, —O—, —S—, —NR^(7.2B)—, —C(O)—, —C(O)O—, —S(O)—,        —S(O)₂—, substituted or unsubstituted alkylene, substituted or        unsubstituted heteroalkylene, substituted or unsubstituted        cycloalkylene, substituted or unsubstituted heterocycloalkylene,        substituted or unsubstituted arylene, or substituted or        unsubstituted heteroarylene;    -   R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1),        —CN, —N₃, —SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C),        —NHNR^(1B)R^(1C), —ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C),        —NHC(O)NR^(1B)R^(1C), —N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D),        —C(O)OR^(1D), —C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A),        —NR^(1B)C(O)R^(1D), —NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D),        —OCX^(1.1) ₃, —OCHX^(1.1) ₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R² is hydrogen, halogen, —CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1),        —CN, —N₃, —SO_(n2)R^(2A), —SO_(v2)NR^(2B)R^(2C),        —NHNR^(2B)R^(2C), —ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C),        —NHC(O)NR^(2B)R^(2C), —N(O)_(m2), —NR^(2B)R^(2C), —C(O)R^(2D),        —C(O)OR^(2D), —C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A),        —NR^(2B)C(O)R^(2D), —NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D),        —OCX^(2.1) ₃, —OCHX^(2.1) ₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R³ is independently hydrogen, halogen, —CX^(3.1) ₃, —CHX^(3.1)        ₂, —CH₂X^(3.1), —CN, —N₃, —SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C),        —NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C),        —NHC(O)NR^(3B)R^(3C), —N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D),        —C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A),        —NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D),        —OCX^(3.1) ₃, —OCHX^(3.1) ₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl or        substituted or unsubstituted heteroaryl;    -   R⁴ is hydrogen, halogen, —CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1),        —CN, —N₃, —SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C),        —NHNR^(4B)R^(4C), —ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C),        —NHC(O)NR^(4B)R^(4C), —N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D),        —C(O)OR^(4D), —C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A),        —NR^(4B)C(O)R^(4D), —NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D),        —OCX^(4.1) ₃, —OCHX^(4.1) ₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl or        substituted or unsubstituted heteroaryl;    -   R⁵ is independently hydrogen, halogen, oxo, —CX^(5.1) ₃,        —CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —N₃, —SO_(n5)R^(5A),        —SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), —ONR^(5B)R^(5C),        —NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C), —N(O)_(m5),        —NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D), —C(O)NR^(5B)R^(5C),        —OR^(5A), —NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D),        —NR^(5B)C(O)OR^(5D), —NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1)        ₂, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   R⁶ is independently hydrogen, halogen, oxo, —CX^(6.1) ₃,        —CHX^(6.1) ₂, —CH₂X^(6.1), —CN, —N₃, —SO_(n6)R^(6A),        —SO_(v6)NR^(6B)R^(6C), —NHNR^(6B)R^(6C), —ONR^(6B)R^(6C),        —NHC(O)NHNR^(6B)R^(6C), —NHC(O)NR^(6B)R^(6C), —N(O)_(m6),        —NR^(6B)R^(6C), —C(O)R^(6D), —C(O)OR^(6D), —C(O)NR^(6B)R^(6C),        —OR^(6A), —NR^(6B)SO₂R^(6A), —NR^(6B)C(O)R^(6D),        —NR^(6B)C(O)OR^(6D), —NR^(6B)OR^(6D), —OCX^(6.1) ₃, —OCHX^(6.1)        ₂, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   R⁷ is hydrogen, halogen, —CX^(7.1) ₃, —CHX^(7.1) ₂, —CH₂X^(7.1),        —CN, —N₃, —SO_(n7)R^(7A), —SO_(v7)NR^(7B)R^(7C),        —NHNR^(7B)R^(7C), —ONR^(7B)R^(7C), —NHC(O)NHNR^(7B)R^(7C),        —NHC(O)NR^(7B)R^(7C), —N(O)_(m7), —NR^(7B)R^(7C), —C(O)R^(7D),        —C(O)OR^(7D), —C(O)NR^(7B)R^(7C), —OR^(7A), —NR^(7B)SO₂R^(7A),        —NR^(7B)C(O)R^(7D), —NR^(7B)C(O)OR^(7D), —NR^(7B)OR^(7D),        —OCX^(7.1) ₃, —OCHX^(7.1) ₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl or        substituted or unsubstituted heteroaryl;    -   R⁸ is hydrogen, halogen, —CX^(8.1) ₃, —CHX^(8.1) ₂, —CH₂X^(8.1),        —CN, —N₃, —SO_(n8)R^(8A), —SO_(v8)NR^(8B)R^(8C),        —NHNR^(8B)R^(8C), —ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C),        —NHC(O)NR^(8B)R^(8C), —N(O)_(m8), —NR^(8B)R^(8C), —C(O)R^(8D),        —C(O)OR^(8D), —C(O)NR^(8B)R^(8C), —OR^(8A), —NR^(8B)SO₂R^(8A),        —NR^(8B)C(O)R^(8D), —NR^(8B)C(O)OR^(8D), —NR^(8B)OR^(8D),        —OCX^(8.1) ₃, —OCHX^(8.1) ₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R⁹ is hydrogen, halogen, —CX^(9.1) ₃, —CHX^(9.1) ₂, —CH₂X^(9.1),        —CN, —N₃, —SO_(n9)R^(9A), —SO_(v9)NR^(9B)R^(9C),        —NHNR^(9B)R^(9C), —ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C),        —NHC(O)NR^(9B)R^(9C), —N(O)_(m9), —NR^(9B)R^(9C), —C(O)R^(9D),        —C(O)OR^(9D), —C(O)NR^(9B)R^(9C), —OR^(9A), —NR^(9B)SO₂R^(9A),        —NR^(9B)C(O)R^(9D), —NR^(9B)C(O)OR^(9D), —NR^(9B)OR^(9D),        —OCX^(9.1) ₃, —OCHX^(9.1) ₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R¹⁰ is hydrogen, halogen, —CX^(10.1) ₃, —CHX^(10.1) ₂,        —CH₂X^(10.1), —CN, —N₃, —SO_(n10)R^(10A),        —SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C), —ONR^(10B)R^(10C),        —NHC(O)NHNR^(10B)R^(10C), —NHC(O)NR^(10B)R^(10C), —N(O)_(m10),        —NR^(10B)R^(10C), —C(O)R^(10D), —C(O)OR^(10D),        —C(O)NR^(10B)R^(10C), —OR^(10A), —NR^(10B)SO₂R^(10A),        —NR^(10B)C(O)R^(10D), —NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D),        —OCX^(10.1) ₃, —OCHX^(10.1) ₂, substituted or unsubstituted        alkyl, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D),        R^(3A), R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D),        R^(5A), R^(5B), R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D),        R^(7A), R^(7B), R^(7C), R^(7D), R^(8A), R^(8B), R^(8C), R^(8D),        R^(9A), R^(9B), R^(9C), R^(9D), R^(10A), R^(10B), R^(10C) and        R^(10D) are independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃,        —CI₃, —COOH, —CONH₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl; R^(1B), R^(1C), R^(2B),        R^(2C), R^(3B), R^(3C), R^(4B), R^(4C), R^(5B), R^(5C), R^(6B),        R^(6C), R^(7B), R^(7C), R^(8B), R^(8C), R^(9B), R^(9C), R^(10B)        and R^(10C) substituents bonded to the same nitrogen atom may        optionally be joined to form a substituted or unsubstituted        heterocycloalkyl or substituted or unsubstituted heteroaryl; and    -   X^(1.1), X^(2.1), X^(3.1), X^(4.1), X^(5.1), X^(6.1), X^(7.1),        X^(8.1), X^(9.1) and X^(10.1) are independently —Cl, —Br, —I or        —F, wherein at least one of X¹, X² and X³ is N.

In embodiments, the compounds of formula (I) are modulators of CCR4activity. In embodiments, the compounds of formula (I) are CCR4antagonists.

In embodiments, pharmaceutically acceptable salts of the compoundsdisclosed in U.S. patent application Ser. No. 15/662,861 filed Jul. 28,2017 of Beck et al. (e.g., for example, compounds of Formulae I throughVII) are used as CCR4 modulators. In embodiments, the CCR4 modulatorsare the compounds selected from the group consisting of:

or a pharmaceutically acceptable salt of any of the foregoing compounds.

Another group of CCR4 modulators are compounds disclosed in U.S. patentapplication Ser. No. 15/700,040 filed Sep. 8, 2017 of Beck et al (e.g.,for example, compounds of Formulae I through X), which are incorporatedherein by reference in its entirety for all purposes. In embodiments,the compounds having Formula II:

or a pharmaceutically acceptable salt thereof,wherein:

A is a substituted or unsubstituted heterocycloalkyl;

X¹ is CR⁸ or N;

X² is CR⁹ or N;

X³ is CR¹⁰ or N;

X⁴ is C, CR¹¹ or N;

z1 is an integer from 0 to 5;

z2 is an integer from 0 to 13;

z3 is an integer from 0 to 12;

z4 is an integer from 0 to 3;

is a single bond or double bond, wherein if

is a single bond, then X⁴ is CR¹¹ or N, and if

is a double bond, then X⁴ is C;

L⁷ is a bond, —O—, —S—, —NR^(7B)—, —C(O)—, —C(O)O—, —S(O)—, —S(O)₂—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, or substituted or unsubstituted heteroarylene;

R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1), —CN,—SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C),—ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), —NHC(O)NR^(1B)R^(1C),—N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D), —C(O)OR^(1D),—C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A), —NR^(1B)C(O)R^(1D),—NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃, —OCHX^(1.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R² is hydrogen, halogen, —CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN,—SO_(n2)R^(2A), —SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C),—ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C),—N(O)_(m2), —NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D),—C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D),—NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R³ is independently hydrogen, halogen, —CX^(3.1) ₃, —CHX^(3.1) ₂,—CH₂X^(3.1), —CN, —SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C),—NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C),—NHC(O)NR^(3B)R^(3C), —N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D),—C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A),—NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃,—OCHX^(3.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl;

R⁴ is hydrogen, halogen, —CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1), —CN,—SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C),—ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C),—N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D),—C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D),—NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl;

R⁵ is independently hydrogen, halogen, oxo, —CX^(5.1) ₃, —CHX^(5.1) ₂,—CH₂X^(5.1), —CN, —SO_(n5)R^(5A), —SO_(v5)NR^(5B)R^(5C),—NHNR^(5B)R^(5C), —ONR^(5B)R^(5C), —NHC(O)NHNR^(5B)R^(5C),—NHC(O)NR^(5B)R^(5C), —N(O)_(m5), —NR^(5B)R^(5C), —C(O)R^(5D),—C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A), —NR^(5B)SO₂R^(5A),—NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D), —NR^(5B)OR^(5D), —OCX^(5.1) ₃,—OCHX^(5.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl;

R⁶ is independently hydrogen, halogen, oxo, —CX^(6.1) ₃, —CHX^(6.1) ₂,—CH₂X^(6.1), —CN, —SO_(n6)R^(6A), —SO_(v6)NR^(6B)R^(6C),—NHNR^(6B)R^(6C), —ONR^(6B)R^(6C), —NHC(O)NHNR^(6B)R^(6C),—NHC(O)NR^(6B)R^(6C), —N(O)_(m6), —NR^(6B)R^(6C), —C(O)R^(6D),—C(O)OR^(6D), —C(O)NR^(6B)R^(6C), —OR^(6A), —NR^(6B)SO₂R^(6A),—NR^(6B)C(O)R^(6D), —NR^(6B)C(O)OR^(6D), —NR^(6B)OR^(6D), —OCX^(6.1) ₃,—OCHX^(6.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl;

R⁸ is hydrogen, halogen, —CX^(8.1) ₃, —CHX^(8.1) ₂, —CH₂X^(8.1), —CN,—SO_(n8)R^(8A), —SO_(v8)NR^(8B)R^(8C), —NHNR^(8B)R^(8C),—ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C), —NHC(O)NR^(8B)R^(8C),—N(O)_(m8), —NR^(8B)R^(8C), —C(O)R^(8D), —C(O)OR^(8D),—C(O)NR^(8B)R^(8C), —OR^(8A), —NR^(8B)SO₂R^(8A), —NR^(8B)C(O)R^(8D),—NR^(8B)C(O)OR^(8D), —NR^(8B)OR^(8D), —OCX^(8.1) ₃, —OCHX^(8.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R⁹ is hydrogen, halogen, —CX^(9.1) ₃, —CHX^(9.1) ₂, —CH₂X^(9.1), —CN,—SO_(n9)R^(9A), —SO_(v9)NR^(9B)R^(9C), —NHNR^(9B)R^(9C),—ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C), —NHC(O)NR^(9B)R^(9C),—N(O)_(m9), —NR^(9B)R^(9C), —C(O)R^(9D), —C(O)OR^(9D),—C(O)NR^(9B)R^(9C), —OR^(9A), —NR^(9B)SO₂R^(9A), —NR^(9B)C(O)R^(9D),—NR^(9B)C(O)OR^(9D), —NR^(9B)OR^(9D), —OCX^(9.1) ₃, —OCHX^(9.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R¹⁰ is hydrogen, halogen, —CX^(10.1) ₃, —CHX^(10.1) ₂, —CH₂X^(10.1),—CN, —SO_(n10)R^(10A), —SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C),—ONR^(10B)R^(10C), —NHC(O)NHNR^(10B)R^(10C), —NHC(O)NR^(10B)R^(10C),—N(O)_(m10), —NR^(10B)R^(10C), —C(O)R^(10D), —C(O)OR^(10D),—C(O)NR^(10B)R^(10C), —OR^(10A), —NR^(10B)SO₂R^(10A),—NR^(10B)C(O)R^(10D), —NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D),—OCX^(10.1) ₃, —OCHX^(10.1) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R¹¹ is hydrogen, halogen, —CX^(11.1) ₃, —CHX^(11.1) ₂, —CH₂X^(11.1),—CN, —SO_(n11)R^(11A), —SO_(v11)NR^(11B)R^(11C), —NHNR^(11B)R^(11C),—ONR^(11B)R^(11C), —NHC(O)NHNR^(11B)R^(11C), —NHC(O)NR^(11B)R^(11C),—N(O)_(m11), —NR^(11B)R^(11C), —C(O)R^(11D), —C(O)OR^(11D),—C(O)NR^(11B)R^(11C), —OR^(11A), —NR^(11B)SO₂R^(11A),—NR^(11B)C(O)R^(11D), —NR^(11B)C(O)OR^(11D), —NR^(11B)OR^(11D),—OCX^(11.1) ₃, —OCHX^(11.1) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A),R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D), R^(5A), R^(5B),R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D), R^(8A), R^(8B), R^(8C),R^(8D), R^(9A), R^(9B), R^(9C), R^(9D), R^(10A), R^(10B), R^(10C),R^(10D), R^(11A), R^(11B), R^(11C) and R^(11D) are independentlyhydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —COOH, —CONH₂, substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(1B) and R^(1C), R^(2B) and R^(2C), R^(3B)and R^(3C), R^(4B) and R^(4C), R^(5B) and R^(5C), R^(6B) and R^(6C),R^(8B) and R^(8C), R^(9B) and R^(9C), R^(10B) and R^(10C), R^(11B) andR^(11C) substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl;

n1, n2, n3, n4, n5, n6, n8, n9, n10 and n11 are independently an integerfrom 0 to 4;

m1, m2, m3, m4, m5, m6, m8, m9, m10, m11, v1, v2, v3, v4, v5, v6, v8,v9, v10, and v11 are independently 1 or 2; and

X^(1.1), X^(2.1), X^(3.1), X^(4.1), X^(5.1), X^(6.1), X^(8.1), X^(9.1),X^(10.1), and X^(11.1) are independently —Cl, —Br, —I or —F, wherein atleast one of X¹, X², and X³ is N.

In embodiments, the compounds of formula (II) are modulators of CCR4activity. In embodiments, the compounds of formula (II) are CCR4antagonists.

In embodiments, pharmaceutically acceptable salts of the compoundsdisclosed in U.S. patent application Ser. No. 15/700,040 filed Sep. 8,2017 of Beck et al. (e.g., for example, compounds of Formulae I throughX) are used as CCR4 modulators. In embodiments, the CCR4 modulators arethe compounds selected from the group consisting of:

or a pharmaceutically acceptable salt of any of the foregoing compounds.

Another group of CCR4 modulators are compounds disclosed in U.S. PatentApplication 62/481,515 filed Apr. 4, 2017, of Beck et al. (e.g., forexample, compounds of Formulae I through VI), which are incorporatedherein by reference in its entirety for all purposes. In embodiments,the compounds having Formula III:

or a pharmaceutically acceptable salt thereof,wherein:

A is substituted or unsubstituted cycloalkyl or substituted orunsubstituted heterocycloalkyl;

X¹ is CR⁸ or N;

X² is CR⁹ or N;

X³ is CR¹⁰ or N;

X⁴ is C, CR¹¹ or N;

X⁷ is NR¹⁷ or N, wherein when L⁷ is covalently bound to X⁷, then X⁷ isN;

n1, n2, n3, n4, n5, n6, n8, n9, n10, n11, and n17 are independently aninteger from 0 to 4;

m1, m2, m3, m4, m5, m6, m8, m9, m10, m11, m17, v1, v2, v3, v4, v5, v6,v8, v9, v10, v11, and v17 are independently 1 or 2;

z1 is an integer from 0 to 5;

z2 is an integer from 0 to 8;

z3 is an integer from 0 to 12;

is a single bond or double bond, wherein if

is a single bond, then X⁴ is CR¹¹ or N, and if

is a double bond, then X⁴ is C;

L⁷ is a bond, —O—, —S—, —NR^(7B)—, —C(O)—, —C(O)O—, —S(O)—, —S(O)₂—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, or substituted or unsubstituted heteroarylene;

R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1), —CN,—SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C),—ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), —NHC(O)NR^(1B)R^(1C),—N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D), —C(O)OR^(1D),—C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A), —NR^(1B)C(O)R^(1D),—NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃, —OCHX^(1.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R² is hydrogen, halogen, —CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN,—SO_(n2)R^(2A), —SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C),—ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C),—N(O)_(m2), —NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D),—C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D),—NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R³ is independently hydrogen, halogen, —CX^(3.1) ₃, —CHX^(3.1) ₂,—CH₂X^(3.1), —CN, —SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C),—NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C),—NHC(O)NR^(3B)R^(3C), —N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D),—C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A),—NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃,—OCHX^(3.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl;

R⁴ is hydrogen, halogen, —CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1), —CN,—SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C),—ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C),—N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D),—C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D),—NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl;

R⁵ is independently hydrogen, halogen, oxo, —CX^(5.1) ₃, —CHX^(5.1) ₂,—CH₂X^(5.1), —CN, —SO_(n5)R^(5A), —SO_(v5)NR^(5B)R^(5C),—NHNR^(5B)R^(5C), —ONR^(5B)R^(5C), —NHC(O)NHNR^(5B)R^(5C),—NHC(O)NR^(5B)R^(5C), —N(O)_(m5), —NR^(5B)R^(5C), —C(O)R^(5D),—C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A), —NR^(5B)SO₂R^(5A),—NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D), —NR^(5B)OR^(5D), —OCX^(5.1) ₃,—OCHX^(5.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl;

R⁶ is independently hydrogen, halogen, oxo, —CX^(6.1) ₃, —CHX^(6.1) ₂,—CH₂X^(6.1), —CN, —SO_(n6)R^(6A), —SO_(v6)NR^(6B)R^(6C),—NHNR^(6B)R^(6C), —ONR^(6B)R^(6C), —NHC(O)NHNR^(6B)R^(6C),—NHC(O)NR^(6B)R^(6C), —N(O)_(m6), —NR^(6B)R^(6C), —C(O)R^(6D),—C(O)OR^(6D), —C(O)NR^(6B)R^(6C), —OR^(6A), —NR^(6B)SO₂R^(6A),—NR^(6B)C(O)R^(6D), —NR^(6B)C(O)OR^(6D), —NR^(6B)OR^(6D), —OCX^(6.1) ₃,—OCHX^(6.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl;

R⁸ is hydrogen, halogen, —CX^(8.1) ₃, —CHX^(8.1) ₂, —CH₂X^(8.1), —CN,—SO_(n8)R^(8A), —SO_(v8)NR^(8B)R^(8C), —NHNR^(8B)R^(8C),—ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C), —NHC(O)NR^(8B)R^(8C),—N(O)_(m8), —NR^(8B)R^(8C), —C(O)R^(8D), —C(O)OR^(8D),—C(O)NR^(8B)R^(8C), —OR^(8A), —NR^(8B)SO₂R^(8A), —NR^(8B)C(O)R^(8D),—NR^(8B)C(O)OR^(8D), —NR^(8B)OR^(8D), —OCX^(8.1) ₃, —OCHX^(8.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R⁹ is hydrogen, halogen, —CX^(9.1) ₃, —CHX^(9.1) ₂, —CH₂X^(9.1), —CN,—SO_(n9)R^(9A), —SO_(v9)NR^(9B)R^(9C), —NHNR^(9B)R^(9C),—ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C), —NHC(O)NR^(9B)R^(9C),—N(O)_(m9), —NR^(9B)R^(9C), —C(O)R^(9D), —C(O)OR^(9D),—C(O)NR^(9B)R^(9C), —OR^(9A), —NR^(9B)SO₂R^(9A), —NR^(9B)C(O)R^(9D),—NR^(9B)C(O)OR^(9D), —NR^(9B)OR^(9D), —OCX^(9.1) ₃, —OCHX^(9.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R¹⁰ is hydrogen, halogen, —CX^(10.1) ₃, —CHX^(10.1) ₂, —CH₂X^(10.1),—CN, —SO_(n10)R^(10A), —SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C),—ONR^(10B)R^(10C), —NHC(O)NHNR^(10B)R^(10C), —NHC(O)NR^(10B)R^(10C),—N(O)_(m10), —NR^(10B)R^(10C), —C(O)R^(10D), —C(O)OR^(10D),—C(O)NR^(10B)R^(10C), —OR^(10A), —NR^(10B)SO₂R^(10A),—NR^(10B)C(O)R^(10D), —NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D),—OCX^(10.1) ₃, —OCHX^(10.1) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R¹¹ is hydrogen, halogen, —CX^(11.1) ₃, —CHX^(11.1) ₂, —CH₂X^(11.1),—CN, —SO_(n11)R^(11A), —SO_(v11)NR^(11B)R^(11C), —NHNR^(11B)R^(11C),—ONR^(11B)R^(11C), —NHC(O)NHNR^(11B)R^(11C), —NHC(O)NR^(11B)R^(11C),—N(O)_(m11), —NR^(11B)R^(11C), —C(O)R^(11D), —C(O)OR^(11D),—C(O)NR^(11B)R^(11C), —OR^(11A), —NR^(11B)SO₂R^(11A),—NR^(11B)C(O)R^(11D), —NR^(11B)C(O)OR^(11D), —NR^(11B)OR^(11D),—OCX^(11.1) ₃, —OCHX^(11.1) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R¹⁷ is hydrogen, halogen, —CX^(17.1) ₃, —CHX^(17.1) ₂, —CH₂X^(17.1),—CN, —SO_(n17)R^(17A), —SO_(v17)NR^(17B)R^(17C), —NHNR^(17B)R^(17C),—ONR^(17B)R^(17C), —NHC(O)NHNR^(17B)R^(17C), —NHC(O)NR^(17B)R^(17C),—N(O)_(m17), —NR^(17B)R^(17C), —C(O)R^(17D), —C(O)OR^(17D),—C(O)NR^(17B)R^(17C), —OR^(17A), —NR^(17B)SO₂R^(17A),—NR^(17B)C(O)R^(17D), —NR^(17B)C(O)OR^(17D), —NR^(17B)OR^(17D),—OCX^(17.1) ₃, —OCHX^(1.1) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A),R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D), R^(5A), R^(5B),R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D), R^(8A), R^(8B), R^(8C),R^(8D), R^(9A), R^(9B), R^(9C), R^(9D), R^(10A), R^(10B), R^(10C),R^(10D), R^(11A), R^(11B), R^(11C), R^(11D), R^(17A), R^(17B), R^(17C)and R^(17D) are independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃,—CI₃, —COOH, —CONH₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R^(1B)and R^(1C), R^(2B) and R^(2C), R^(3B) and R^(3C), R^(4B) and R^(4C),R^(5B) and R^(5C), R^(6B) and R^(6C), R^(8B) and R^(8C), R^(9B) andR^(9C), R^(10B) and R^(10C) R^(11B) and R^(11C) and R^(17B) and R^(17C)substituents bonded to the same nitrogen atom may optionally be joinedto form a substituted or unsubstituted heterocycloalkyl or substitutedor unsubstituted heteroaryl; and

X^(1.1), X^(2.1), X^(3.1), X^(4.1), X^(5.1), X^(6.1), X^(8.1), X^(9.1),X^(10.1), X^(11.1) and X^(17.1) are independently —Cl, —Br, —I or —F,wherein at least one of X¹, X² and X³ is N.

In embodiments, the compounds of formula (III) are modulators of CCR4activity. In embodiments, the compounds of formula (III) are CCR4antagonists.

In embodiments, pharmaceutically acceptable salts of the compoundsdisclosed in U.S. Patent Application 62/481,515 filed Apr. 4, 2017 ofBeck et al (e.g., for example, compounds of Formulae I through VI) areused as CCR4 modulators. In embodiments, the CCR4 modulators are thecompounds selected from the group consisting of:

or a pharmaceutically acceptable salt of any of the foregoing compounds.

Another group of CCR4 modulators are compounds disclosed in U.S. PatentApplication 62/622,774 filed Jan. 26, 2018, of Robles-Resendiz et al.(e.g., for example, compounds of Formulae I through VII), which areincorporated herein by reference in its entirety for all purposes. Inembodiments, the compounds having Formula IV:

or a pharmaceutically acceptable salt thereof,wherein:

X¹ is CR⁸ or N;

X² is CR⁹ or N;

X³ is CR¹⁰ or N;

n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, and n44 are independently aninteger from 0 to 4;

m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, v1, v2, v3, v4, v5, v6, v7, v8,v9, v10, and v44 are independently 1 or 2;

z1 is an integer from 0 to 5;

z2 is an integer from 0 to 4;

z3 is an integer from 0 to 11;

z4 is an integer from 0 to 2;

L⁷ is a bond, —O—, —S—, —NR^(7.2B)—, —C(O)—, —C(O)O—, —S(O)—, —S(O)₂—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, or substituted or unsubstituted heteroarylene;

R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1), —CN,—N₃, —SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C),—ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), —NHC(O)NR^(1B)R^(1C),—N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D), —C(O)OR^(1D),—C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A), —NR^(1B)C(O)R^(1D),—NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃, —OCHX^(1.1) ₂,—OCH₂X^(1.1), substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl;

R² is hydrogen, halogen, —CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN,—N₃, —SO_(n2)R^(2A), —SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C),—ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C),—N(O)_(m2), —NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D),—C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D),—NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂,—OCH₂X^(2.1), substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl;

R³ is independently halogen, —CX^(3.1) ₃, —CHX^(3.1) ₂, —CH₂X^(3.1),—CN, —N₃, —SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C),—ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C), —NHC(O)NR^(3B)R^(3C),—N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D), —C(O)OR^(3D),—C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A), —NR^(3B)C(O)R^(3D),—NR^(3B)C(O)R^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃, —OCHX^(3.2),—OCH₂X^(3.1), substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl;

R⁴ is hydrogen, halogen, —CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1), —CN,—N₃, —SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C),—ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C),—N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D),—C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D),—NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂,—OCH₂X^(4.1), substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl, or whenX² is CR⁹, then R⁴ and R⁹ may optionally be joined to form a substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl;

R⁵ is independently halogen, oxo, —CX^(5.1) ₃, —CHX^(5.1) ₂,—CH₂X^(5.1), —CN, —N₃, —SO_(n5)R^(5A), —SO_(v5)NR^(5B)R^(5C),—NHNR^(5B)R^(5C), —ONR^(5B)R^(5C), —NHC(O)NHNR^(5B)R^(5C),—NHC(O)NR^(5B)R^(5C), —N(O)_(m5), —NR^(5B)R^(5C), —C(O)R^(5D),—C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A), —NR^(5B)SO₂R^(5A),—NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D), —NR^(5B)OR^(5D), —OCX^(5.1) ₃,—OCHX^(5.1) ₂, —OCH₂X^(5.1), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl or substituted or unsubstituted heteroaryl;

R⁶ is independently halogen, oxo, —CX^(6.1) ₃, —CHX^(6.1) ₂,—CH₂X^(6.1), —CN, —N₃, —SO_(n6)R^(6A), —SO_(v6)NR^(6B)R^(6C),—NHNR^(6B)R^(6C), —ONR^(6B)R^(6C), —NHC(O)NHNR^(6B)R^(6C),—NHC(O)NR^(6B)R^(6C), —N(O)_(m6), —NR^(6B)R^(6C), —C(O)R^(6D),—C(O)OR^(6D), —C(O)NR^(6B)R^(6C), —OR^(6A), —NR^(6B)SO₂R^(6A),—NR^(6B)C(O)R^(6D), —NR^(6B)C(O)OR^(6D), —NR^(6B)OR^(6D), —OCX^(6.1) ₃,—OCHX^(6.1) ₂, —OCH₂X^(6.1), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl or substituted or unsubstituted heteroaryl;

R⁷ is hydrogen, halogen, —CX^(7.1) ₃, —CHX^(7.1) ₂, —CH₂X^(7.1), —CN,—N₃, —SO_(n7)R^(7A), —SO_(v7)NR^(7B)R^(7C), —NHNR^(7B)R^(7C),—ONR^(7B)R^(7C), —NHC(O)NHNR^(7B)R^(7C), —NHC(O)NR^(7B)R^(7C),—N(O)_(m7), —NR^(7B)R^(7C), —C(O)R^(7D), —C(O)OR^(7D),—C(O)NR^(7B)R^(7C), —OR^(7A), —NR^(7B)SO₂R^(7A), —NR^(7B)C(O)R^(7D),—NR^(7B)C(O)OR^(7D), —NR^(7B)OR^(7D), —OCX^(7.1) ₃, —OCHX^(7.1) ₂,—OCH₂X^(7.1), substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl;

R⁸ is hydrogen, halogen, —CX^(8.1) ₃, —CHX^(8.1) ₂, —CH₂X^(8.1), —CN,—N₃, —SO_(n8)R^(8A), —SO_(v8)NR^(8B)R^(8C), —NHNR^(8B)R^(8C),—ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C), —NHC(O)NR^(8B)R^(8C),—N(O)_(m8), —NR^(8B)R^(8C), —C(O)R^(8D), —C(O)OR^(8D),—C(O)NR^(8B)R^(8C), —OR^(8A), —NR^(8B)SO₂R^(8A), —NR^(8B)C(O)R^(8D),—NR^(8B)C(O)OR^(8D), —NR^(8B)OR^(8D), —OCX^(8.1) ₃, —OCHX^(8.1) ₂,—OCH₂X^(8.1), substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl;

R⁹ is hydrogen, halogen, —CX^(9.1) ₃, —CHX^(9.1) ₂, —CH₂X^(9.1), —CN,—N₃, —SO₉R^(9A), —SO_(v9)NR^(9B)R^(9C), —NHNR^(9B)R^(9C),—ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C), —NHC(O)NR^(9B)R^(9C),—N(O)_(m9), —NR^(9B)R^(9C), —C(O)R^(9D), —C(O)OR^(9D),—C(O)NR^(9B)R^(9C), —OR^(9A), —NR^(9B)SO₂R^(9A), —NR^(9B)C(O)R^(9D),—NR^(9B)C(O)OR^(9D), —NR^(9B)OR^(9D), —OCX^(9.1) ₃, —OCHX^(9.1) ₂,—OCH₂X^(9.1), substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl, or whenX² is CR⁹, then R⁴ and R⁹ may optionally be joined to form a substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; or when X² is CR⁹ and X³ is CR¹⁰, then R⁹ andR¹⁰ may optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, orunsubstituted aryl, or substituted or unsubstituted heteroaryl;

R¹⁰ is hydrogen, halogen, —CX^(10.1) ₃, —CHX^(10.1) ₂, —CH₂X^(10.1),—CN, —N₃, —SO_(n10)R^(10A), —SO_(v10)NR^(10B)R^(10C),—NHNR^(10B)R^(10C), —ONR^(10B)R^(10C), —NHC(O)NHNR^(10B)R^(10C),—NHC(O)NR^(10B)R^(10C), —N(O)_(m10), —NR^(10B)R^(10C), —C(O)R^(10D),—C(O)OR^(10D), —C(O)NR^(10B)R^(10C), —OR^(10A), —NR^(10B)SO₂R^(10A),—NR^(10B)C(O)R^(10D), —NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D),—OCX^(10.1) ₃, —OCHX^(10.1) ₂, —OCH₂X^(10.1), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; or when X² is CR⁹ and X³ is CR¹⁰, then R⁹ andR¹⁰ may optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, orunsubstituted aryl, or substituted or unsubstituted heteroaryl;

R⁴⁴ is hydrogen, —CX^(44.1) ₃, —CHX^(44.1) ₂, —CH₂X^(44.1),—SO_(n44)R^(44A), —SO_(v44)NR^(44B)R^(44C), —C(O)R^(44D), —C(O)OR^(44D),—C(O)NR^(44B)R^(44C), substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl;

R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A),R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D), R^(5A), R^(5B),R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D), R^(7A), R^(7B), R^(7C),R^(7D), R^(7.2B), R^(8A), R^(8B), R^(8C), R^(8D), R^(9A), R^(9B),R^(9C), R^(9D), R^(10A), R^(10B), R^(10C), R^(10D), R^(44A), R^(44B),R^(44C), and R^(44D) are independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —COOH, —CONH₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(1B), R^(1C), R^(2B), R^(2C), R^(3B), R^(3C), R^(4B), R^(4C), R^(5B),R^(5C), R^(6B), R^(6C), R^(7B), R^(7C), R^(8B), R^(8C), R^(9B), R^(9C),R^(10B), R^(10C), R^(44B), and R^(44C) substituents bonded to the samenitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; and

X^(1.1), X^(2.1), X^(3.1), X^(4.1), X^(5.1), X^(6.1), X^(7.1), X^(8.1),X^(9.1), X^(10.1), and X^(44.1) are independently —Cl, —Br, —I or —F;

wherein at least one of X¹, X² and X³ is N.

In embodiments, the compounds of formula (IV) are modulators of CCR4activity. In embodiments, the compounds of formula (IV) are CCR4antagonists.

In embodiments, pharmaceutically acceptable salts of the compoundsdisclosed in U.S. Patent Application 62/622,774 filed Jan. 26, 2018, ofRobles-Resendiz et al. (e.g., for example, compounds of Formulae Ithrough VII) are used as CCR4 modulators. In embodiments, the CCR4modulators are the compounds selected from the group consisting of:

or a pharmaceutically acceptable salt of any of the foregoing compounds.

Another group of CCR4 modulators are compounds disclosed in U.S. PatentApplication 62/622,771 filed Jan. 26, 2018, of Jackson et al., which areincorporated herein by reference in its entirety for all purposes. Inembodiments, the compound having Formula V:

or a pharmaceutically acceptable salt thereof.

In embodiments, the compounds of formula (V) are modulators of CCR4activity. In embodiments, the compounds of formula (V) are CCR4antagonists.

In embodiments, pharmaceutically acceptable salts of the compoundsdisclosed in U.S. Patent Application 62/622,771 filed Jan. 26, 2018, ofJackson et al. are used as CCR4 modulators. In embodiments, the CCR4modulator is the compound of formula V:

Additional orally administered CCR4 modulators include the compoundsdisclosed in the following published patent applications: US2012/0015932 (Hobbs et al); US 2010/0144759 (Cheshire et al); US2008/0293742 (Cheshire et al); US 2006/0189613 (Cheshire); US2006/0128723 (Mete et al); US 2006/0122195 (Harrison et al); US2006/0004010 (Habashita et al); US 2004/0039035 (Collins et al); US2003/0018022 (Collins et al); US 2002/0173524 (Collins et al); US2002/0132836 (Dairaghi et al); U.S. Pat. Nos. 5,300,498; 6,509,357; US2003/149018; WO 01/005758; WO 03/051876; WO 97/042174; WO 2006/101456;WO 2007/065683; WO 2007/065924; WO 2007/115231; WO 2008/045529; WO2008/094575; WO 2008/094602; WO 2010/118367; and WO 2013/082429, all ofwhich are incorporated herein by reference in their entireties.

Parenterally Administered CCR4 Modulators

The CCR4 modulator used in the presently disclosed therapeutic methodscan also be a CCR4-binding antibody. Such antibodies are disclosed inthe following published patent applications: US 2017/0290911 (Marasco etal); US 2017/0088627 (Lin et al); US 2016/0185865 (Marasco et al); US2015/0147321 (Ishii et al); US 2013/0295045 (Shitara et al); US2007/0031896 (Wu et al); US 2007/0020263 (Shitara et al); and US2005/0287138 (Lida et al), all of which are incorporated herein byreference in their entireties.

In certain embodiments herein provide salts, cocrystals, solvates (e.g.,hydrates), complexes, prodrugs, precursors, metabolites, and/or otherderivatives of a CCR4 modulator provided herein. For example, particularembodiments provide salts, cocrystals, solvates (e.g., hydrates),complexes, precursors, metabolites, and/or other derivatives of a CCR4modulator. Certain embodiments provide a CCR4 modulator that is notsalts, cocrystals, solvates (e.g., hydrates), or complexes of a CCR4modulator provided herein. For example, particular embodiments provide aCCR4 modulator in a non-ionized, non-solvated (e.g., anhydrous),non-complexed form.

It should be noted that if there is a discrepancy between a depictedstructure and a chemical name given that structure, the depictedstructure is to be accorded more weight. In addition, if thestereochemistry of a structure or a portion of a structure is notindicated with, for example, bold or dashed lines, the structure orportion of the structure is to be interpreted as encompassing allstereoisomers. Where the compound provided herein contains an alkenyl oralkenylene group, the compound may exist as one geometric (i.e.,cis/trans or E/Z) isomer or a mixture of geometric (i.e., cis/trans orE/Z) isomers. Unless otherwise specified, a compound provided herein isintended to encompass all geometric isomers.

Where structural isomers are inter-convertible, the compound may existas a single tautomer or a mixture of tautomers. This can take the formof proton tautomerism in the compound that contains, for example, animino, keto, or oxime group; or so-called valence tautomerism in thecompound that contain, for example, an aromatic moiety. It follows thata single compound may exhibit more than one type of isomerism. It willbe understood that unless otherwise specified, a compound providedherein is intended to encompass all possible tautomers. Similarly,unless otherwise specified, a compound provided herein is intended toencompass all possible stereoisomers.

The compounds provided herein may be enantiomerically pure, such as asingle enantiomer or a single diastereomer, or be stereoisomericmixtures, such as a mixture of enantiomers, e.g., a racemic mixture oftwo enantiomers; or a mixture of two or more diastereomers. Conventionaltechniques for the preparation/isolation of individual enantiomersinclude synthesis from a suitable optically pure precursor, asymmetricsynthesis from achiral starting materials, or resolution of anenantiomeric mixture, for example, by chiral chromatography,recrystallization, resolution, diastereomeric salt formation, orderivatization into diastereomeric adducts followed by separation. Insome instances, for compounds that undergo epimerization in vivo, one ofskill in the art will recognize that administration of a compound in its(R) form is equivalent to administration of the compound in its (S)form, and vice versa.

When the compound provided herein contains an acidic or basic moiety, itmay also be provided as a pharmaceutically acceptable salt (See, Bergeet al., J. Pharm. Sci. 1977, 66, 1-19; and “Handbook of PharmaceuticalSalts, Properties, and Use,” Stahl and Wermuth, Ed.; Wiley-VCH and VHCA,Zurich, 2002).

Suitable acids for use in the preparation of pharmaceutically acceptablesalts include, but are not limited to, acetic acid, 2,2-dichloroaceticacid, acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, boric acid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid,D-glucuronic acid, L-glutamic acid, .alpha.-oxoglutaric acid, glycolicacid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodicacid, (+)-L-lactic acid, (.+−.)-DL-lactic acid, lactobionic acid, lauricacid, maleic acid, (−)-L-malic acid, malonic acid, (.+−.)-DL-mandelicacid, methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid,saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid,stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaricacid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, andvaleric acid.

Suitable bases for use in the preparation of pharmaceutically acceptablesalts, including, but not limited to, inorganic bases, such as magnesiumhydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, orsodium hydroxide; and organic bases, such as primary, secondary,tertiary, and quaternary, aliphatic and aromatic amines, includingL-arginine, benethamine, benzathine, choline, deanol, diethanolamine,diethylamine, dimethylamine, dipropylamine, diisopropylamine,2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine,isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine,morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine,piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine,pyridine, quinuclidine, quinoline, isoquinoline, secondary amines,triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

The compound provided herein may also be provided as a prodrug, which isa functional derivative of a compound provided herein, and is readilyconvertible into the parent compound in vivo. Prodrugs are often usefulbecause, in some situations, they may be easier to administer than theparent compound. They may, for instance, be bioavailable by oraladministration whereas the parent compound is not. The prodrug may alsohave enhanced solubility in pharmaceutical compositions over the parentcompound. A prodrug may be converted into the parent drug by variousmechanisms, including enzymatic processes and metabolic hydrolysis. SeeHarper, Progress in Drug Research 1962, 4, 221-294; Morozowich et al. in“Design of Biopharmaceutical Properties through Prodrugs and Analogs,”Roche Ed., APHA Acad. Pharm. Sci. 1977; “Bioreversible Carriers in Drugin Drug Design, Theory and Application,” Roche Ed., APHA Acad. Pharm.Sci. 1987; “Design of Prodrugs,” Bundgaard, Elsevier, 1985; Wang et al.,Curr. Pharm. Design 1999, 5, 265-287; Pauletti et al., Adv. Drug.Delivery Rev. 1997, 27, 235-256; Mizen et al., Pharm. Biotech. 1998, 11,345-365; Gaignault et al., Pract. Med. Chem. 1996, 671-696; Asgharnejadin “Transport Processes in Pharmaceutical Systems,” Amidon et al., Ed.,Marcell Dekker, 185-218, 2000; Balant et al., Eur. J. Drug Metab.Pharmacokinet. 1990, 15, 143-53; Balimane and Sinko, Adv. Drug DeliveryRev. 1999, 39, 183-209; Browne, Clin. Neuropharmacol. 1997, 20, 1-12;Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39; Bundgaard, Controlled DrugDelivery 1987, 17, 179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8,1-38; Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130;Fleisher et al., Methods Enzymol. 1985, 112, 360-381; Farquhar et al.,J. Pharm. Sci. 1983, 72, 324-325; Freeman et al., J. Chem. Soc., Chem.Commun. 1991, 875-877; Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4,49-59; Gangwar et al., Des. Biopharm. Prop. Prodrugs Analogs, 1977,409-421; Nathwani and Wood, Drugs 1993, 45, 866-94; Sinhababu andThakker, Adv. Drug Delivery Rev. 1996, 19, 241-273; Stella et al., Drugs1985, 29, 455-73; Tan et al., Adv. Drug Delivery Rev. 1999, 39, 117-151;Taylor, Adv. Drug Delivery Rev. 1996, 19, 131-148; Valentino andBorchardt, Drug Discovery Today 1997, 2, 148-155; Wiebe and Knaus, Adv.Drug Delivery Rev. 1999, 39, 63-80; and Waller et al., Br. J. Clin.Pharmac. 1989, 28, 497-507.

Pharmaceutical Compositions

In an aspect, provided are compositions for treatment of EBV+malignancies. The compounds (the compound of formulae (I), (II), (III),(IV), or (V)) of the present disclosure may be in the form ofcompositions suitable for administration to a subject. In general, suchcompositions are “pharmaceutical compositions” comprising a compound(e.g., the compound of formulae (I), (II), (III), (IV), or (V)) and oneor more pharmaceutically acceptable or physiologically acceptablediluents, carriers or excipients. In certain embodiments, the compound(e.g., the compound of formulae (I), (II), (III), (IV), or (V)) ispresent in a therapeutically acceptable amount. The pharmaceuticalcompositions may be used in the methods of the present disclosure; thus,for example, the pharmaceutical compositions can be administered ex vivoor in vivo to a subject in order to practice the therapeutic andprophylactic methods and uses described herein.

The pharmaceutical compositions of the present disclosure can beformulated to be compatible with the intended method or route ofadministration; exemplary routes of administration are set forth herein.

The pharmaceutical compositions containing the active ingredient (e.g.,the compound of formulae (I), (II), (III), (IV), or (V) may be in a formsuitable for oral use, for example, as tablets, capsules, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups, solutions, microbeads orelixirs. Pharmaceutical compositions intended for oral use may beprepared according to any method known to the art for the manufacture ofpharmaceutical compositions, and such compositions may contain one ormore agents such as, for example, sweetening agents, flavoring agents,coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets, capsulesand the like contain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture thereof. These excipients may be, for example, diluents,such as calcium carbonate, sodium carbonate, lactose, calcium phosphateor sodium phosphate; granulating and disintegrating agents, for example,corn starch, or alginic acid; binding agents, for example starch,gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid or talc.

The tablets, capsules and the like suitable for oral administration maybe uncoated or coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction. For example, a time-delay material such as glyceryl monostearateor glyceryl distearate may be employed. They may also be coated bytechniques known in the art to form osmotic therapeutic tablets forcontrolled release. Additional agents include biodegradable orbiocompatible particles or a polymeric substance such as polyesters,polyamine acids, hydrogel, polyvinyl pyrrolidone, polyanhydrides,polyglycolic acid, ethylene-vinylacetate, methylcellulose,carboxymethylcellulose, protamine sulfate, or lactide/glycolidecopolymers, polylactide/glycolide copolymers, or ethylenevinylacetatecopolymers in order to control delivery of an administered composition.For example, the oral agent can be entrapped in microcapsules preparedby coacervation techniques or by interfacial polymerization, by the useof hydroxymethylcellulose or gelatin-microcapsules orpoly(methylmethacrylate) microcapsules, respectively, or in a colloiddrug delivery system. Colloidal dispersion systems include macromoleculecomplexes, nano-capsules, microspheres, microbeads, and lipid-basedsystems, including oil-in-water emulsions, micelles, mixed micelles, andliposomes. Methods for the preparation of the above-mentionedformulations will be apparent to those skilled in the art.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate, kaolin ormicrocrystalline cellulose, or as soft gelatin capsules wherein theactive ingredient is mixed with water or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture thereof. Such excipients can besuspending agents, for example sodium carboxymethyl cellulose,methylcellulose, hydroxy-propylmethyl cellulose, sodium alginate,polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents, for example a naturally-occurring phosphatide (e.g.,lecithin), or condensation products of an alkylene oxide with fattyacids (e.g., polyoxy-ethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols (e.g., forheptadecaethyleneoxycetanol), or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol (e.g.,polyoxyethylene sorbitol monooleate), or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides (e.g., polyethylene sorbitan monooleate). The aqueoussuspensions may also contain one or more preservatives.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents, such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation.Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, and optionally one or moresuspending agents and/or preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified herein.

The pharmaceutical compositions of the present disclosure may also be inthe form of oil-in-water emulsions. The oily phase may be a vegetableoil, for example olive oil or arachis oil, or a mineral oil, forexample, liquid paraffin, or mixtures of these. Suitable emulsifyingagents may be naturally occurring gums, for example, gum acacia or gumtragacanth; naturally occurring phosphatides, for example, soy bean,lecithin, and esters or partial esters derived from fatty acids; hexitolanhydrides, for example, sorbitan monooleate; and condensation productsof partial esters with ethylene oxide, for example, polyoxyethylenesorbitan monooleate.

The pharmaceutical compositions typically comprise a therapeuticallyeffective amount of a CCR4 modulator contemplated by the presentdisclosure and one or more pharmaceutically and physiologicallyacceptable formulation agents. Suitable pharmaceutically acceptable orphysiologically acceptable diluents, carriers or excipients include, butare not limited to, antioxidants (e.g., ascorbic acid and sodiumbisulfate), preservatives (e.g., benzyl alcohol, methyl parabens, ethylor n-propyl, p-hydroxybenzoate), emulsifying agents, suspending agents,dispersing agents, solvents, fillers, bulking agents, detergents,buffers, vehicles, diluents, and/or adjuvants. For example, a suitablevehicle may be physiological saline solution or citrate-buffered saline,possibly supplemented with other materials common in pharmaceuticalcompositions for parenteral administration. Neutral buffered saline orsaline mixed with serum albumin are further exemplary vehicles. Thoseskilled in the art will readily recognize a variety of buffers that canbe used in the pharmaceutical compositions and dosage forms contemplatedherein. Typical buffers include, but are not limited to,pharmaceutically acceptable weak acids, weak bases, or mixtures thereof.As an example, the buffer components can be water soluble materials suchas phosphoric acid, tartaric acids, lactic acid, succinic acid, citricacid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, andsalts thereof. Acceptable buffering agents include, for example, a Trisbuffer; N-(2-Hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) (HEPES);2-(N-Morpholino)ethanesulfonic acid (MES);2-(N-Morpholino)ethanesulfonic acid sodium salt (MES);3-(N-Morpholino)propanesulfonic acid (MOPS); andN-tris[Hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

After a pharmaceutical composition has been formulated, it may be storedin sterile vials as a solution, suspension, gel, emulsion, solid, ordehydrated or lyophilized powder. Such formulations may be stored eitherin a ready-to-use form, a lyophilized form requiring reconstitutionprior to use, a liquid form requiring dilution prior to use, or otheracceptable form. In some embodiments, the pharmaceutical composition isprovided in a single-use container (e.g., a single-use vial, ampule,syringe, or autoinjector (similar to, e.g., an EpiPen®)), whereas amulti-use container (e.g., a multi-use vial) is provided in otherembodiments.

Formulations can also include carriers to protect the compositionagainst rapid degradation or elimination from the body, such as acontrolled release formulation, including liposomes, hydrogels, prodrugsand microencapsulated delivery systems. For example, a time-delaymaterial such as glyceryl monostearate or glyceryl stearate alone, or incombination with a wax, may be employed. Any drug delivery apparatus maybe used to deliver a CCR4 modulator, including implants (e.g.,implantable pumps) and catheter systems, slow injection pumps anddevices, all of which are well known to the skilled artisan.

Depot injections, which are generally administered subcutaneously orintramuscularly, may also be utilized to release the compound (e.g.,CCR4 modulator) disclosed herein over a defined period of time. Depotinjections are usually either solid- or oil-based and generally compriseat least one of the formulation components set forth herein. One ofordinary skill in the art is familiar with possible formulations anduses of depot injections.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents mentioned herein. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example, as a solution in 1,3-butane diol. Acceptable diluents,solvents and dispersion media that may be employed include water,Ringer's solution, isotonic sodium chloride solution, Cremophor® EL(BASF, Parsippany, N.J.) or phosphate buffered saline (PBS), ethanol,polyol (e.g., glycerol, propylene glycol, and liquid polyethyleneglycol), and suitable mixtures thereof. In addition, sterile fixed oilsare conventionally employed as a solvent or suspending medium; for thispurpose, any bland fixed oil may be employed, including synthetic mono-or diglycerides. Moreover, fatty acids, such as oleic acid, find use inthe preparation of injectables. Prolonged absorption of particularinjectable formulations can be achieved by including an agent thatdelays absorption (e.g., aluminum monostearate or gelatin).

The present disclosure contemplates the administration of the compound(e.g., CCR4 modulator) in the form of suppositories for rectaladministration. The suppositories can be prepared by mixing the drugwith a suitable non-irritating excipient which is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Such materials include, but arenot limited to, cocoa butter and polyethylene glycols.

The compound (e.g., CCR4 modulator) contemplated by the presentdisclosure may be in the form of any other suitable pharmaceuticalcomposition (e.g., sprays for nasal or inhalation use) currently knownor developed in the future.

Additional Therapeutic Agents

In some embodiments, provided herein is a pharmaceutical compositioncomprising one, two, three, or more other pharmacologically activesubstances (also termed herein “additional therapeutic agents,” “secondactive agents,” or the like) (e.g., other than a CCR4 modulator). Insome embodiments, the formulations of the compound of formulae (I),(II), (III), (IV), or (V) provided herein further comprise one, two,three, or more other pharmacologically active substances (also termedherein “additional therapeutic agents,” “second active agents,” or thelike). In other embodiments, the formulation of the compound of formulae(I), (II), (III), (IV), or (V) provided herein is co-administered withone, two, three, or more other pharmacologically active substances. Inparticular embodiments, the oral formulations provided herein comprisethe additional therapeutic agent(s) in a therapeutically effectiveamount. In particular embodiments, the formulations of the compound offormulae (I), (II), (III), (IV), or (V) and the additional therapeuticagent(s) are co-formulated together in the same dosage form usingmethods of co-formulating active pharmaceutical ingredients, includingmethods disclosed herein and methods known in the art. In otherembodiments, the formulations of the compound of formulae (I), (II),(III), (IV), or (V) and the additional therapeutic agent(s) areco-administered in separate dosage forms. It is believed that certaincombinations work synergistically in the treatment of particulardiseases or disorders, including, e.g., types of EBV-associated cancerand certain diseases and conditions associated with, or characterizedby, undesired angiogenesis or abnormal cell proliferation, for example,solid tumors. The formulations of the compound of formulae (I), (II),(III), (IV), or (V) provided herein can also work to alleviate adverseeffects associated with certain second active agents, and some secondactive agents can be used to alleviate adverse effects associated with aCCR4 modulator dosage forms provided herein. In certain embodiments, theformulations of a CCR4 modulator provided herein are co-administeredwith one or more therapeutic agents to provide a resensitization effectin subjects in need thereof. Additional therapeutic agents can be, e.g.,large molecules (e.g., proteins) or small molecules (e.g., syntheticinorganic, organometallic, or organic molecules).

Examples of particular additional therapeutic agents useful in thecompositions and methods disclosed herein include, but are not limitedto, e.g., cytotoxic agents, anti-metabolites, antifolates, HDACinhibitors (e.g., entinostat, also known as SNDX-275 or MS-275; orvorinostat, also known as suberoylanilide hydroxamic acid (SAHA) orN-hydroxy-N-phenyl-octanediamide), DNA intercalating agents, DNAcross-linking agents, DNA alkylating agents, DNA cleaving agents,topoisomerase inhibitors, HDAC inhibitors such as MGCD0103 (a.k.a.N-(2-aminophenyl)-4-((4-(pyridin-3-yl)pyrimidin-2-ylamino)methyl)benzamid-e),CDK inhibitors, JAK inhibitors, anti-angiogenic agents, Bcr-Ablinhibitors, HER2 inhibitors, EGFR inhibitors, VEGFR inhibitors, PDGFRinhibitors, HGFR inhibitors, IGFR inhibitors, c-Kit inhibitors, Raspathway inhibitors, PI3K inhibitors, multi-targeted kinase inhibitors,mTOR inhibitors, anti-estrogens, anti-androgens, aromatase inhibitors,somatostatin analogs, ER modulators, anti-tubulin agents, vincaalkaloids, taxanes, HSP inhibitors, Smoothened antagonists, telomeraseinhibitors, COX-2 inhibitors, anti-metastatic agents,immunosuppressants, biologics such as antibodies, and hormonaltherapies. In particular embodiments, the co-administered therapeuticagent is an immunomodulator. In specific embodiments, theimmunomodulatory compound is thalidomide, lenalidomide, or pomalidomide.In particular embodiments, the co-administered therapeutic agent iscarboplatin. In particular embodiments, the co-administered therapeuticagent is paclitaxel (e.g., Abraxane®). See, e.g., U.S. Pat. Nos.7,758,891, 7,771,751, 7,820,788, 7,923,536, 8,034,375; US PatentPublication Nos. 2007/0082838 and 2010/0048499; U.S. Pat. Nos.5,916,596; 6,506,405; 6,749,868, and 6,537,579; PCT Publication Nos.WO08/057562, WO09/126938, WO09/126401, and WO09/126175; all of which areincorporated herein by reference in their entireties.

In embodiments, the co-administered agent may be dosed orally. Inanother embodiment, the co-administered agent may be dosed by injection.In one embodiment, the route of the administration of the compound offormulae (I), (II), (III), (IV), or (V) is independent of the route ofthe administration of the second/co-administered therapy. In oneembodiment, the compound of formulae (I), (II), (III), (IV), or (V) isadministered orally. In another embodiment, the compound of formulae(I), (II), (III), (IV), or (V) is administered intravenously orsubcutaneously. In certain embodiments, the compound of formulae (I),(II), (III), (IV), or (V) is administered orally, and the second therapyis administered orally, parenterally, intraperitoneally, intravenously,intraarterially, transdermally, sublingually, intramuscularly, rectally,transbuccally, intranasally, liposomally, via inhalation, vaginally,intraoccularly, via local delivery by catheter or stent, subcutaneously,intraadiposally, intraarticularly, intrathecally, or in a slow releasedosage form. In one embodiment, the compound of formulae (I), (II),(III), (IV), or (V) and a second therapy agent are administered by thesame mode of administration, e.g., orally, intravenously, orsubcutaneously. In another embodiment, the compound of formulae (I),(II), (III), (IV), or (V) is administered by one mode of administration,e.g., orally, whereas the second agent (e.g., an anticancer agent) isadministered by another mode of administration, e.g., intravenously orsubcutaneously. In yet another embodiment, the compound of formulae (I),(II), (III), (IV), or (V) is administered by one mode of administration,e.g., intravenously or subcutaneously, whereas the second agent (e.g.,an anticancer agent) is administered by another mode of administration,e.g., orally.

Other examples of additional therapeutic agents include, but are notlimited to, hematopoietic growth factor, a cytokine, granulocytecolony-stimulating factor (G-CSF), granulocyte-macrophagecolony-stimulating factor (GM-CSF), erythropoietin (EPO), interleukin(IL), interferon (IFN), oblimersen, melphalan, topotecan,pentoxifylline, taxotere, irinotecan, ciprofloxacin, doxorubicin,vincristine, dacarbazine, Ara-C, vinorelbine, prednisone,cyclophosphamide, bortezomib, arsenic trioxide. Such additionaltherapeutic agents are particularly useful in methods and compositionsdisclosed herein including, but not limited to, those relating totreatment of Burkitt lymphoma, Hodgkin lymphoma, diffuse large B-celllymphoma, NK/T-cell lymphoma, cutaneous T-cell lymphoma, nasopharyngealcarcinoma and gastric cancer.

Other examples of additional therapeutic agents include, but are notlimited to, an antibody (e.g., rituximab, anti-CD33), hematopoieticgrowth factor, cytokine, antibiotic, cox-2 inhibitor, immunomodulatoryagent, immunosuppressive agent, corticosteroid, or a pharmacologicallyactive mutant or derivative thereof. See, e.g., S. Nand et al., Leukemiaand Lymphoma, 2008, 49(11):2141-47 (describing a Phase II studyinvolving the administration of a combination of hydroxyurea,azacitidine and low dose gemtuzumab ozogamicin to elderly patients withAML and high-risk MDS, and concluding that this combination appears tobe a safe and effective regimen in the treatment of AML and high riskMDS in this group of patients). Such additional therapeutic agents areparticularly useful in methods and compositions disclosed hereinincluding, but not limited to, those relating to treatment of thediseases and disorders disclosed herein.

Examples of large molecule active agents include, but are not limitedto, hematopoietic growth factors, cytokines, and monoclonal andpolyclonal antibodies. Typical large molecule active agents arebiological molecules, such as naturally occurring or artificially madeproteins. Proteins that are particularly useful include proteins thatstimulate the survival and/or proliferation of hematopoietic precursorcells and immunologically active poietic cells in vitro or in vivo.Others stimulate the division and differentiation of committed erythroidprogenitors in cells in vitro or in vivo. Particular proteins include,but are not limited to: interleukins, such as IL-2 (includingrecombinant IL-II (“rIL2”) and canarypox IL-2), IL-10, IL-12, and IL-18;interferons, such as interferon alfa-2a, interferon alfa-2b, interferonalfa-n1, interferon alfa-n3, interferon beta-I a, and interferon gamma-Ib; GM-CF and GM-CSF; and EPO.

Particular proteins that can be used in the methods and compositionsprovided herein include, but are not limited to: filgrastim, which issold in the United States under the trade name Neupogen®. (Amgen,Thousand Oaks, Calif.); sargramostim, which is sold in the United Statesunder the trade name Leukine®. (Immunex, Seattle, Wash.); andrecombinant EPO, which is sold in the United States under the trade nameEpogen®. (Amgen, Thousand Oaks, Calif.).

Recombinant and mutated forms of GM-CSF can be prepared as described inU.S. Pat. Nos. 5,391,485; 5,393,870; and 5,229,496; all of which areincorporated herein by reference. Recombinant and mutated forms of G-CSFcan be prepared as described in U.S. Pat. Nos. 4,810,643; 4,999,291;5,528,823; and 5,580,755; all of which are incorporated herein byreference.

Embodiments herein encompass the use of native, naturally occurring, andrecombinant proteins. Particular embodiments encompass mutants andderivatives (e.g., modified forms) of naturally occurring proteins thatexhibit, in vivo, at least some of the pharmacological activity of theproteins upon which they are based. Examples of mutants include, but arenot limited to, proteins that have one or more amino acid residues thatdiffer from the corresponding residues in the naturally occurring formsof the proteins. Also encompassed by the term “mutants” are proteinsthat lack carbohydrate moieties normally present in their naturallyoccurring forms (e.g., nonglycosylated forms). Examples of derivativesinclude, but are not limited to, pegylated derivatives and fusionproteins, such as proteins formed by fusing IgG1 or IgG3 to the proteinor active portion of the protein of interest. See, e.g., Penichet, M. L.and Morrison, S. L., J. Immunol. Methods 248:91-101 (2001).

Antibodies that can be co-administered with the compound of formulae(I), (II), (III), (IV), or (V) include monoclonal and polyclonalantibodies. Examples of antibodies include, but are not limited to,trastuzumab (Herceptin®), rituximab (Rituxan®), bevacizumab (Avastin™),pertuzumab (Omnitarg™), tositumomab (Bexxar®), edrecolomab (Panorex®),nivolumab (Opdivo™), pembrolizumab (Keytruda™), avelumab (Bavencio™)atezolizumab (Tecentriq™), durvalumab (Imfinzi™) and ipilimumab(Yervoy™) and G250. Oral formulations disclosed herein can alsocomprise, be combined with, or used in combination with anti-TNF-αantibodies.

Large molecule active agents may be administered in the form ofanti-cancer vaccines. For example, vaccines that secrete, or cause thesecretion of, cytokines such as IL-2, G-CSF, and GM-CSF can be used inthe methods, pharmaceutical compositions, and kits provided herein. See,e.g., Emens, L. A., et al., Curr. Opinion Mol. Ther. 3(1):77-84 (2001).

In embodiments, the additional therapeutic agent (e.g., large-moleculecompound or small-molecule compound) reduces, eliminates, or prevents anadverse effect associated with the administration (e.g., oraladministration) of the compound of formulae (I), (II), (III), (IV), or(V) as described herein. Depending on the disease or disorder begintreated, adverse effects of the compound of formulae (I), (II), (III),(IV), or (V) can include, but are not limited to, anemia, neutropenia,febrile neutropenia, thrombocytopenia, hepatotoxicity (e.g., including,but not limited to, hepatoxicity in patients with preexisting hepaticimpairment), elevated serum creatinine, renal failure, renal tubularacidosis, hypokalemia, hepatic coma, nausea, vomiting, dyspepsia,abdominal pain, pyrexia, leukopenia, diarrhea, constipation, ecchymosis,petechiae, rigors, weakness, pneumonia, anxiety, insomnia, lethargy, anddecrease in weight, among others known in the art to be associated withadministration of a CCR4 modulator.

Like some large molecules, many small-molecule compounds are believed tobe capable of providing a synergistic effect when administered with(e.g., before, after or simultaneously) the compound of formulae (I),(II), (III), (IV), or (V) as disclosed herein. Examples of smallmolecule second active agents include, but are not limited to,anti-cancer agents, antibiotics, immunosuppressive agents,immunostimulatory agents and steroids.

Examples of anti-cancer agents include, but are not limited to:acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin;aldesleukin; altretamine; ambomycin; ametantrone acetate; amsacrine;anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa;azotomycin; batimastat; benzodepa; bicalutamide; bisantrenehydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate;brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone;caracemide; carbetimer; carboplatin; carmustine; carubicinhydrochloride; carzelesin; cedefingol; celecoxib (COX-2 inhibitor);chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin;enpromate; epipropidine; epirubicin hydrochloride; erbulozole;esorubicin hydrochloride; estramustine; estramustine phosphate sodium;etanidazole; etoposide; etoposide phosphate; etoprine; fadrozolehydrochloride; fazarabine; fenretinide; floxuridine; fludarabinephosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel;pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; safingol; safingol hydrochloride; semustine;simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur;teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicinhydrochloride.

Other anti-cancer drugs include, but are not limited to: 20-epi-1,25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-1; antiandrogen, prostaticcarcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-a CCR4 modulator;dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel;docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene;dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine;edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride;estramustine analogue; estrogen agonists; estrogen antagonists;etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine;fenretinide; filgrastim; finasteride; flavopiridol; flezelastine;fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex;formestane; fostriecin; fotemustine; gadolinium texaphyrin; galliumnitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine;glutathione inhibitors; hepsulfam; heregulin; hexamethylenebisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;idramantone; ilmofosine; ilomastat; imatinib (e.g., Gleevec®),imiquimod; immunostimulant peptides; insulin-like growth factor-1receptor inhibitor; interferon agonists; interferons; interleukins;iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine;isobengazole; isohomohalicondrin B; itasetron; jasplakinolide;kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin;lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemiainhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; loxoribine; lurtotecan; lutetiumtexaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A;marimastat; masoprocol; maspin; matrilysin inhibitors; matrixmetalloproteinase inhibitors; menogaril; merbarone; meterelin;methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine;mirimostim; mitoguazone; mitolactol; mitomycin analogues; mitonafide;mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene;molgramostim; Erbitux, human chorionic gonadotrophin; monophosphoryllipid A+myobacterium cell wall sk; mopidamol; mustard anticancer agent;mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxidemodulators; nitroxide antioxidant; nitrullyn; oblimersen (Genasense®);O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rohitukine;romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin;SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine;senescence derived inhibitor 1; sense oligonucleotides; signaltransduction inhibitors; sizofuran; sobuzoxane; sodium borocaptate;sodium phenylacetate; solverol; somatomedin binding protein; sonermin;sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin1; squalamine; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; tallimustine; tamoxifen methiodide; tauromustine;tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomeraseinhibitors; temoporfin; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; translation inhibitors; tretinoin;triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron;turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors;ubenimex; urogenital sinus-derived growth inhibitory factor; urokinasereceptor antagonists; vapreotide; variolin B; velaresol; veramine;verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

Specific additional therapeutic agents include, but are not limited to,oblimersen (Genasense®), remicade, docetaxel, celecoxib, melphalan,dexamethasone (Decadron®), steroids, gemcitabine, cisplatinum,temozolomide, etoposide, cyclophosphamide, temodar, carboplatin,procarbazine, gliadel, tamoxifen, topotecan, methotrexate, Arisa®,taxol, taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-11,interferon alpha, pegylated interferon alpha (e.g., PEG INTRON-A),capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomaldaunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2,GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin,busulphan, prednisone, bisphosphonate, arsenic trioxide, vincristine,doxorubicin (Doxil), paclitaxel, ganciclovir, adriamycin, estramustinesodium phosphate (Emcyt®), sulindac, and etoposide.

Methods of Use

In an aspect, provided herein are methods for treating or managingEBV-associated cancer by administering the compound of formulae (I),(II), (III), (IV), or (V), or a pharmaceutically acceptable saltthereof, to a subject having the cancer. In one embodiment, the methodscomprise treating EBV-associated cancer with the compound of formulae(I), (II), (III), (IV), or (V), or a pharmaceutically acceptable saltthereof. In one embodiment, the methods comprise managing EBV-associatedcancer with the compound of formulae (I), (II), (III), (IV), or (V), ora pharmaceutically acceptable salt thereof. In certain embodiments, themethods comprise co-administering one or more additional active agents(e.g., an anti-cancer agent as disclosed herein). In certainembodiments, the subject is a mammal. In certain embodiments, thesubject is a human. In particular embodiments, the EBV-associated canceris a solid tumor (e.g., a relapsed or refractory solid tumor).

In embodiments, provided herein is the use of the compound of formulae(I), (II), (III), (IV), or (V), or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for the treatment and/ormanagement of EBV-associated cancer (e.g., a relapsed or refractorysolid tumor).

In embodiments, provided herein is the compound of formulae (I), (II),(III), (IV), or (V), or a pharmaceutically acceptable salt thereof, foruse in the treatment and/or management of EBV-associated cancer (e.g., arelapsed or refractory solid tumor).

In embodiments, provided herein are methods of treating or managingcertain types of EBV-associated cancers, including but not limited to,an EBV-associated solid tumor; a refractory EBV-associated cancer or arelapsed EBV-associated cancer; or a refractory EBV-associated solidtumor or a relapsed EBV-associated solid tumor. In one embodiment,provided herein are methods of treating or managing certain types ofEBV-associated cancer, including, but not limited to, Burkitt lymphoma,Hodgkin lymphoma, diffuse large B-cell lymphoma, NK/T-cell lymphoma,cutaneous T-cell lymphoma, nasopharyngeal carcinoma, gastric cancer,vulvar squamous cell carcinoma, salivary gland cancer, orbit choroidalmelanoma, and adenocarcinoma consistent with pancreaticobiliary.

In embodiments, provided herein are methods of treating or managingEBV-associated cancers, including Burkitt's lymphoma, Hodgkin lymphoma,diffuse large B-cell lymphoma, NK/T-cell lymphoma, cutaneous T-celllymphoma, nasopharyngeal carcinoma, gastric cancer, vulvar squamous cellcarcinoma, salivary gland cancer, orbit choroidal melanoma, andadenocarcinoma consistent with pancreaticobiliary. In embodiments,provided herein are methods of treating or managing adenocarcinomaconsistent with pancreatiocobilary.

In embodiments, provided herein are methods of treating or managinglymphoma. In embodiments, provided herein are methods of treating ormanaging Burkitt's lymphoma.

In embodiments, provided herein are methods of treating or managingnasopharyngeal carcinoma. In one embodiment, the nasopharyngealcarcinoma is keratinizing squaous-cell carcinoma (formerly WHO type I).In one embodiment, the nasopharyngeal carcinoma is non-keratinizingcarcinoma. In one embodiment, the nasopharyngeal carcinoma is basaloidsquamous cell carcinoma. In one embodiment, the non-keratinizingcarcinoma is differentiated non-keratinizing carcinoma (formerly WHOtype II). In one embodiment, the non-keratinizing carcinoma isundifferentiated non-keratinizing carcinoma (formerly WHO type III).

In embodiments, the methods comprise treating or managing certain stagesof EBV-associated cancer, e.g., Stage 0, Stage I, Stage II, Stage III,and Stage IV, by administering the compound of formulae (I), (II),(III), (IV), or (V), or a pharmaceutically acceptable salt thereof, to asubject having such a cancer. The staging of cancer may be definedaccording to methods known in the art, for example, according to theguidelines provided by the American Joint Committee on Cancer (AJCC). Inone embodiment, the staging of cancer is designated and grouped based onthe TNM classification, i.e., a classification based on the status ofprimary tumor (e.g., TX, T0, Tis, T1, T2, T3, T4), regional lymph nodes(e.g., NX, N0, N1, N2, N3), and/or distant metastasis (e.g., MX, M0,M1), in a subject having EBV-associated cancer.

Particular embodiments provide treating a subject having EBV-associatedcancer using one or more of the methods provided herein, together withsurgery. Particular embodiments provide treating a subject havingEBV-associated cancer using one or more of the methods provided herein,together with chemotherapy. Particular embodiments provide treating asubject having EBV-associated cancer using one or more of the methodsprovided herein, together with immunotherapy. Particular embodimentsprovide treating a subject having EBV-associated cancer using one ormore of the methods provided herein, together with targeted therapy.Particular embodiments provide treating a subject having EBV-associatedcancer using one or more of the methods provided herein, together withradiation therapy. Particular embodiments provide treating a subjecthaving EBV-associated cancer using one or more of the methods providedherein, together with cellular therapy. Particular embodiments providetreating a subject having EBV-associated cancer using one or more of themethods provided herein, together with vaccination therapy. Particularembodiments provide treating a subject having EBV-associated cancerusing one or more of the methods provided herein, together with genetherapy. Particular embodiments provide treating a subject havingEBV-associated cancer using one or more of the methods provided herein,together with two or more of the treatments selected from surgery,chemotherapy, immunotherapy, targeted therapy, radiation therapy,cellular therapy, vaccination therapy or gene therapy. Particularembodiments provide treating a subject having EBV-associated cancerusing one or more of the methods provided herein, together with two ormore of the treatments selected from surgery, chemotherapy,immunotherapy and radiation therapy.

In embodiments, the subject to be treated with one of the methodsprovided herein has not been treated with anticancer therapy prior tothe administration of the compound of formulae (I), (II), (III), (IV),or (V). In certain embodiments, the subject to be treated with one ofthe methods provided herein has been treated with one or more anticancertherapies prior to the administration of the compound of formulae (I),(II), (III), (IV), or (V). In certain embodiments, the subject to betreated with one of the methods provided herein has been treated with acancer therapeutic agent, as described herein. In certain embodiments,the subject to be treated with one of the methods provided herein hasdeveloped drug resistance to anticancer therapy. In certain embodiments,the subject to be treated with the methods provided herein has arelapsed EBV-associated cancer. In certain embodiments, the subject tobe treated with the methods provided herein has a refractoryEBV-associated cancer. In certain embodiments, the subject to be treatedwith the methods provided herein has a metastatic EBV-associated cancer.In certain embodiments, the subject to be treated with the methodsprovided herein has EBV-associated lymphoma. In certain embodiments, thesubject to be treated with the methods provided herein has Burkitt'slymphoma.

In embodiments, the methods provided herein encompass treating a subjectregardless of patient's age, although some diseases or disorders aremore common in certain age groups. Further provided herein is a methodfor treating a subject who has undergone surgery in an attempt to treatthe disease or condition at issue. Further provided herein is a methodfor treating a subject who has not undergone surgery as an attempt totreat the disease or condition at issue. Because the subjects withEBV-associated cancer have heterogeneous clinical manifestations andvarying clinical outcomes, the treatment given to a particular subjectmay vary, depending on his/her prognosis. The skilled clinician will beable to readily determine without undue experimentation, specificsecondary agents, types of surgery, and types of non-drug based standardtherapy that can be effectively used to treat an individual subject withEBV-associated cancer.

In embodiments provided herein, the method may further comprise one ormore diagnostic steps, to determine, e.g., the type of EBV-associatedcancer, the presence of particular cell types, the genetic profile of asubject, and/or the staging of the disease in a subject.

In embodiments provided herein, the method may further comprise adisease evaluation step after the compound of formulae (I), (II), (III),(IV), or (V) has been administered to the subject, to determine, e.g.,changes in one or more molecular markers as described herein elsewhere,changes in tumor size and location, and/or other benchmarks used bythose skilled in the art to determine the prognosis of EBV-associatedcancer in a subject.

Embodiments herein provide administration of the compound of formulae(I), (II), (III), (IV), or (V) by, e.g., intravenous (IV), subcutaneous(SC) or oral routes of administration. Certain methods herein provideadministration of the compound of formulae (I), (II), (III), (IV), or(V) by oral route of administration. Certain embodiments herein provideco-administration of the compound of formulae (I), (II), (III), (IV), or(V) with one or more additional active agents to provide a synergistictherapeutic effect in subjects in need thereof. The co-administeredagent(s) may be a cancer therapeutic agent, as described herein. Incertain embodiments, the co-administered agent(s) may be dosed, e.g.,orally or by injection (e.g., IV or SC).

Embodiments herein provide methods for treating disorders of abnormalcell proliferation comprising administering the compound of formulae(I), (II), (III), (IV), or (V) using, e.g., IV, SC and/or oraladministration methods. Certain embodiments herein provide methods fortreating disorders of abnormal cell proliferation comprisingadministering the compound of formulae (I), (II), (III), (IV), or (V)using oral administration methods. In certain embodiments, treatmentcycles comprise multiple doses administered to a subject in need thereofover multiple days (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or greater than28 days), optionally followed by treatment dosing holidays (e.g., 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, or greater than 28 days). Suitable dosageamounts for the methods provided herein include, e.g., therapeuticallyeffective amounts and prophylactically effective amounts. In specificembodiments, a treatment cycle comprises multiple doses administered toa subject in need thereof once a day or more than once a day, for 3days, for 5 days, for 7 days, for 14 days, for 21 days, or for 28 days.In specific embodiments, a treatment cycle comprises a resting period of1 day, 2 days, 3 days, 4 days, 5 days, 7 days, 14 days, 21 days, or 28days. In specific embodiments, a subject is treated with multipletreatment cycles, for example, multiple 7-day, 14-day, 21-day, 28-day,35-day, or 42-day treatment cycles for a total period of treatment ofabout 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, or 24 months, or greater than 24 months. In specificembodiments, a subject is treated with multiple treatment cycles, thatmay be the same or different (e.g., a 7-day treatment cycle followed bya 14-day, 21-day, or 28-day treatment cycle).

In embodiments, the amount of the compound of formulae (I), (II), (III),(IV), or (V) administered in the methods provided herein may range,e.g., between about 1 mg/day and about 2,000 mg/day, between about 1mg/day and about 1,000 mg/day, between about 50 mg/day and about 500mg/day, or between about 100 mg/day and about 400 mg/day. In certainembodiments, particular dosages are, e.g., about 50 mg/day, about 75mg/day, about 100 mg/day, about 120 mg/day, about 140 mg/day, about 160mg/day, about 180 mg/day, about 200 mg/day, about 220 mg/day, about 240mg/day, about 240 mg/day, about 260 mg/day, about 280 mg/day, about 300mg/day, about 320 mg/day, about 340 mg/day, about 360 mg/day, about 380mg/day, about 400 mg/day, about 420 mg/day, about 440 mg/day, about 460mg/day, about 480 mg/day, or about 500 mg/day. In certain embodiments,particular dosages are, e.g., up to about 50 mg/day, up to about 75mg/day, up to about 100 mg/day, up to about 125 mg/day, up to about 150mg/day, up to about 175 mg/day, up to about 200 mg/day, up to about 225mg/day, up to about 250 mg/day, up to about 275 mg/day, up to about 300mg/day, up to about 325 mg/day, up to about 350 mg/day, up to about 325mg/day, up to about 350 mg/day, up to about 375 mg/day, up to about 400mg/day, up to about 425 mg/day, up to about 450 mg/day, up to about 475mg/day, up to about 500 mg/day, up to about 750 mg/day, or up to about1000 mg/day.

In embodiments, depending on the disease to be treated and the subject'scondition, the compound of formulae (I), (II), (III), (IV), or (V) maybe administered by oral, parenteral (e.g., intramuscular,intraperitoneal, intravenous, CIV, intracisternal injection or infusion,subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal,sublingual, or topical (e.g., transdermal or local) routes ofadministration. In some embodiments, the compound of formulae (I), (II),(III), (IV), or (V) may be formulated, alone or together with one ormore active agent(s), in suitable dosage unit with pharmaceuticallyacceptable excipients, carriers, adjuvants and vehicles, appropriate foreach route of administration. In one embodiment, the compound offormulae (I), (II), (III), (IV), or (V) is administered orally. Inanother embodiment, the compound of formulae (I), (II), (III), (IV), or(V) is administered parenterally. In yet another embodiment, thecompound of formulae (I), (II), (III), (IV), or (V) is administeredintravenously. In yet another embodiment, the compound of formulae (I),(II), (III), (IV), or (V) is administered subcutaneously.

In embodiments the compound of formulae (I), (II), (III), (IV), or (V)is delivered as a single dose such as, e.g., a single bolus injection,or oral tablets or pills; or over time such as, e.g., continuousinfusion over time or divided bolus doses over time. In embodiments, thecompound of formulae (I), (II), (III), (IV), or (V) is administeredrepetitively if necessary, for example, until the patient experiencesstable disease or regression, or until the patient experiences diseaseprogression or unacceptable toxicity. For example, stable disease forsolid tumors generally means that the perpendicular diameter ofmeasurable lesions has not increased by 25% or more from the lastmeasurement. See, e.g., Response Evaluation Criteria in Solid Tumors(RECIST) Guidelines, Journal of the National Cancer Institute 92(3):205-216 (2000). Stable disease or lack thereof is determined by methodsknown in the art such as evaluation of patient's symptoms, physicalexamination, visualization of the tumor that has been imaged usingX-ray, CAT, PET, or MRI scan and other commonly accepted evaluationmodalities.

In embodiments, the compound of formulae (I), (II), (III), (IV), or (V)is administered once daily (QD), or divided into multiple daily dosessuch as twice daily (BID), three times daily (TID), and four times daily(QID). In embodiments, the administration is continuous (i.e., daily forconsecutive days or every day), or intermittent, e.g., in cycles (i.e.,including days, weeks, or months of rest when no drug is administered).In embodiments, the compound of formulae (I), (II), (III), (IV), or (V)is administered daily, for example, once or more than once each day fora period of time. In embodiments, the compound of formulae (I), (II),(III), (IV), or (V) is administered daily for an uninterrupted period ofat least 7 days, in some embodiments, up to 52 weeks. In embodiments,the compound of formulae (I), (II), (III), (IV), or (V) is administeredintermittently, i.e., stopping and starting at either regular orirregular intervals. In embodiments, the compound of formulae (I), (II),(III), (IV), or (V) is administered for one to six days per week. Inembodiments, the compound of formulae (I), (II), (III), (IV), or (V) isadministered in cycles (e.g., daily administration for about one, two,three, four, five, six, seven, or eight consecutive weeks, then a restperiod with no administration for about one, two, three, or four weeks).In embodiments, the compound of formulae (I), (II), (III), (IV), or (V)is administered on alternate days. In embodiments, the compound offormulae (I), (II), (III), (IV), or (V) is administered in cycles (e.g.,administered daily or continuously for a certain period interrupted witha rest period).

In embodiments, the frequency of administration ranges from about dailyto about monthly. In certain embodiments, the compound of formulae (I),(II), (III), (IV), or (V) is administered once a day, twice a day, threetimes a day, four times a day, once every other day, twice a week, onceevery week, once every two weeks, once every three weeks, or once everyfour weeks. In embodiments, the compound of formulae (I), (II), (III),(IV), or (V) is administered once a day. In embodiments, the compound offormulae (I), (II), (III), (IV), or (V) is administered twice a day. Inembodiments, the compound of formulae (I), (II), (III), (IV), or (V) isadministered three times a day. In embodiments, the compound of formulae(I), (II), (III), (IV), or (V) is administered four times a day.

In embodiments, the compound of formulae (I), (II), (III), (IV), or (V)is administered once per day from one day to six months, from one weekto three months, from one week to four weeks, from one week to threeweeks, or from one week to two weeks. In certain embodiments, thecompound of formulae (I), (II), (III), (IV), or (V) is administered onceper day for one week, two weeks, three weeks, or four weeks. Inembodiments, the compound of formulae (I), (II), (III), (IV), or (V) isadministered once per day for one week. In embodiments, the compound offormulae (I), (II), (III), (IV), or (V) is administered once per day fortwo weeks. In embodiments, the compound of formulae (I), (II), (III),(IV), or (V) is administered once per day for three weeks. Inembodiments, the compound of formulae (I), (II), (III), (IV), or (V) isadministered once per day for four weeks.

In embodiments, the compound of formulae (I), (II), (III), (IV), or (V)is administered once per day for about 1 week, about 2 weeks, about 3weeks, about 4 weeks, about 6 weeks, about 9 weeks, about 12 weeks,about 15 weeks, about 18 weeks, about 21 weeks, or about 26 weeks. Incertain embodiments, the compound of formulae (I), (II), (III), (IV), or(V) is administered intermittently. In certain embodiments, the compoundof formulae (I), (II), (III), (IV), or (V) is administeredintermittently in the amount of between about 50 mg/day and about 1,000mg/day. In certain embodiments, the compound of formulae (I), (II),(III), (IV), or (V) is administered intermittently in the amount ofbetween about 100 mg/day and about 500 mg/day. In certain embodiments,the compound of formulae (I), (II), (III), (IV), or (V) is administeredcontinuously. In certain embodiments, the compound of formulae (I),(II), (III), (IV), or (V) is administered continuously in the amount ofbetween about 50 mg/day and about 1,000 mg/day. In certain embodiments,the compound of formulae (I), (II), (III), (IV), or (V) is administeredcontinuously in the amount of between about 100 mg/day and about 500mg/day.

In certain embodiments, the compound of formulae (I), (II), (III), (IV),or (V) is administered to a patient in cycles. Cycling therapy involvesthe administration of an active agent for a period of time, followed bya rest for a period of time, and repeating this sequentialadministration. Cycling therapy can reduce the development ofresistance, avoid or reduce the side effects, and/or improves theefficacy of the treatment.

Kits

In another aspect, provided herein is a kit including the compound offormulae (I), (II), (III), (IV), or (V) as described herein orpharmaceutical compositions thereof. The kits are generally in the formof a physical structure housing various components, as described below,and may be utilized, for example, in practicing the methods describedherein.

In embodiments, a kit includes one or more of the compound of formulae(I), (II), (III), (IV), or (V) disclosed herein (e.g., provided in asterile container), which may be in the form of a pharmaceuticalcomposition suitable for administration to a subject. The compoundsdescribed herein can be provided in a form that is ready for use (e.g.,an oral formulation such as a tablet or capsule or an injectable formsuch as a sterile solution) or in a form requiring, for example,reconstitution or dilution (e.g., a powder) prior to administration. Inembodiments, when the compound of formulae (I), (II), (III), (IV), or(V) is in a form that needs to be reconstituted or diluted by a user,the kit also includes diluents (e.g., sterile water), buffers,pharmaceutically acceptable excipients, and the like, packaged with, orseparately from, the compound. In embodiments, each component of the kitmay be enclosed within an individual container, and all of the variouscontainers may be within a single package. In embodiments, a kit of thepresent disclosure may be designed for conditions necessary to properlymaintain the components housed therein (e.g., refrigeration orfreezing).

In embodiments, a kit contains a label or packaging insert includingidentifying information for the components therein and instructions fortheir use (e.g., dosing parameters, clinical pharmacology of the activeingredient(s), including mechanism of action, pharmacokinetics andpharmacodynamics, adverse effects, contraindications, etc.). Labels orinserts include manufacturer information such as lot numbers andexpiration dates. In embodiments, the label or packaging insert isintegrated into the physical structure housing the components, containedseparately within the physical structure, or affixed to a component ofthe kit (e.g., an ampule, tube or vial).

In embodiments, labels or inserts additionally include, or beincorporated into, a computer readable medium, such as a disk (e.g.,hard disk, card, memory disk), optical disk such as CD- or DVD-ROM/RAM,DVD, MP3, magnetic tape, or an electrical storage media such as RAM andROM or hybrids of these such as magnetic/optical storage media, FLASHmedia or memory-type cards. In some embodiments, the actual instructionsare not present in the kit, but means for obtaining the instructionsfrom a remote source, e.g., via the internet, are provided.

P EMBODIMENTS Embodiment P1

A method of treating a malignancy that is positive for Epstein BarrVirus (EBV), the method comprising administering to a subject in needthereof a therapeutically effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X¹ is CR⁸ or N;    -   X² is CR⁹ or N;    -   X³ is CR¹⁰ or N;    -   n1, n2, n3, n4, n5, n6, n7, n8, n9 and n10 are independently an        integer from 0 to 4;    -   m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, v1, v2, v3, v4, v5, v6,        v7, v8, v9 and v10 are independently 1 or 2;    -   z1 is an integer from 0 to 5;    -   z2 is an integer from 0 to 2;    -   z3 is an integer from 0 to 11;    -   z4 is an integer from 0 to 2;    -   L⁷ is a bond, —O—, —S—, —NR^(7.2B)—, —C(O)—, —C(O)O—, —S(O)—,        —S(O)₂—, substituted or unsubstituted alkylene, substituted or        unsubstituted heteroalkylene, substituted or unsubstituted        cycloalkylene, substituted or unsubstituted heterocycloalkylene,        substituted or unsubstituted arylene, or substituted or        unsubstituted heteroarylene;    -   R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1),        —CN, —N₃, —SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C),        —NHNR^(1B)R^(1C), —ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C),        —NHC(O)NR^(1B)R^(1C), —N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D),        —C(O)OR^(1D), —C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A),        —NR^(1B)C(O)R^(1D), —NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D),        —OCX^(1.1) ₃, —OCHX^(1.1) ₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R² is hydrogen, halogen, —CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1),        —CN, —N₃, —SO_(n2)R^(2A), —SO_(v2)NR^(2B)R^(2C),        —NHNR^(2B)R^(2C), —ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C),        —NHC(O)NR^(2B)R^(2C), —N(O)_(m2), —NR^(2B)R^(2C), —C(O)R^(2D),        —C(O)OR^(2D), —C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A),        —NR^(2B)C(O)R^(2D), —NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D),        —OCX^(2.1) ₃, —OCHX^(2.1) ₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R³ is independently hydrogen, halogen, —CX^(3.1) ₃, —CHX^(3.1)        ₂, —CH₂X^(3.1), —CN, —N₃, —SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C),        —NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C),        —NHC(O)NR^(3B)R^(3C), —N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D),        —C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A),        —NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D),        —OCX^(3.1) ₃, —OCHX^(3.1) ₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl or        substituted or unsubstituted heteroaryl;    -   R⁴ is hydrogen, halogen, —CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1),        —CN, —N₃, —SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C),        —NHNR^(4B)R^(4C), —ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C),        —NHC(O)NR^(4B)R^(4C), —N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D),        —C(O)OR^(4D), —C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A),        —NR^(4B)C(O)R^(4D), —NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D),        —OCX^(4.1) ₃, —OCHX^(4.1) ₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl or        substituted or unsubstituted heteroaryl;    -   R⁵ is independently hydrogen, halogen, oxo, —CX^(5.1) ₃,        —CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —N₃, —SO_(n5)R^(5A),        —SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), —ONR^(5B)R^(5C),        —NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C), —N(O)_(m5),        —NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D), —C(O)NR^(5B)R^(5C),        —OR^(5A), —NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D),        —NR^(5B)C(O)OR^(5D), —NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1)        ₂, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   R⁶ is independently hydrogen, halogen, oxo, —CX^(6.1) ₃,        —CHX^(6.1) ₂, —CH₂X^(6.1), —CN, —N₃, —SO_(n6)R^(6A),        —SO_(v6)NR^(6B)R^(6C), —NHNR^(6B)R^(6C), —ONR^(6B)R^(6C),        —NHC(O)NHNR^(6B)R^(6C), —NHC(O)NR^(6B)R^(6C), —N(O)_(m6),        —NR^(6B)R^(6C), —C(O)R^(6D), —C(O)OR^(6D), —C(O)NR^(6B)R^(6C),        —OR^(6A), —NR^(6B)SO₂R^(6A), —NR^(6B)C(O)R^(6D),        —NR^(6B)C(O)OR^(6D), —NR^(6B)OR^(6D), —OCX^(6.1) ₃, —OCHX^(6.1)        ₂, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   R⁷ is hydrogen, halogen, —CX^(7.1) ₃, —CHX^(7.1) ₂, —CH₂X^(7.1),        —CN, —N₃, —SO_(n7)R^(7A), —SO_(v7)NR^(7B)R^(7C),        —NHNR^(7B)R^(7C), —ONR^(7B)R^(7C), —NHC(O)NHNR^(7B)R^(7C),        —NHC(O)NR^(7B)R^(7C), —N(O)_(m7), —NR^(7B)R^(7C), —C(O)R^(7D),        —C(O)OR^(7D), —C(O)NR^(7B)R^(7C), —OR^(7A), —NR^(7B)SO₂R^(7A),        —NR^(7B)C(O)R^(7D), —NR^(7B)C(O)OR^(7D), —NR^(7B)OR^(7D),        —OCX^(7.1) ₃, —OCHX^(7.1) ₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl or        substituted or unsubstituted heteroaryl;    -   R⁸ is hydrogen, halogen, —CX^(8.1) ₃, —CHX^(8.1) ₂, —CH₂X^(8.1),        —CN, —N₃, —SO_(n8)R^(8A), —SO_(v8)NR^(8B)R^(8C),        —NHNR^(8B)R^(8C), —ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C),        —NHC(O)NR^(8B)R^(8C), —N(O)_(m8), —NR^(8B)R^(8C), —C(O)R^(8D),        —C(O)OR^(8D), —C(O)NR^(8B)R^(8C), —OR^(8A), —NR^(8B)SO₂R^(8A),        —NR^(8B)C(O)R^(8D), —NR^(8B)C(O)OR^(8D), —NR^(8B)OR^(8D),        —OCX^(8.1) ₃, —OCHX^(8.1) ₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R⁹ is hydrogen, halogen, —CX^(9.1) ₃, —CHX^(9.1) ₂, —CH₂X^(9.1),        —CN, —N₃, —SO_(n9)R^(9A), —SO_(v9)NR^(9B)R^(9C),        —NHNR^(9B)R^(9C), —ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C),        —NHC(O)NR^(9B)R^(9C), —N(O)_(m9), —NR^(9B)R^(9C), —C(O)R^(9D),        —C(O)OR^(9D), —C(O)NR^(9B)R^(9C), —OR^(9A), —NR^(9B)SO₂R^(9A),        —NR^(9B)C(O)R^(9D), —NR^(9B)C(O)OR^(9D), —NR^(9B)OR^(9D),        —OCX^(9.1) ₃, —OCHX^(9.1) ₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R¹⁰ is hydrogen, halogen, —CX^(10.1) ₃, —CHX^(10.1) ₂,        —CH₂X^(10.1), —CN, —N₃, —SO_(n10)R^(10A),        —SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C), —ONR^(10B)R^(10C),        —NHC(O)NHNR^(10B)R^(10C), —NHC(O)NR^(10B)R^(10C), —N(O)_(m10),        —NR^(10B)R^(10C), —C(O)R^(10D), —C(O)OR^(10D),        —C(O)NR^(10B)R^(10C), —OR^(10A), —NR^(10B)SO₂R^(10A),        —NR^(10B)C(O)R^(10D), —NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D),        —OCX^(10.1) ₃, —OCHX^(10.1) ₂, substituted or unsubstituted        alkyl, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D),        R^(3A), R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D),        R^(5A), R^(5B), R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D),        R^(7A), R^(7B), R^(7C), R^(7D), R^(8A), R^(8B), R^(8C), R^(8D),        R^(9A), R^(9B), R^(9C), R^(9D), R^(10A), R^(10B), R^(10C) and        R^(10D) are independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃,        —CI₃, —COOH, —CONH₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl; R^(1B), R^(1C), R^(2B),        R^(2C), R^(3B), R^(3C), R^(4B), R^(4C), R^(5B), R^(5C), R^(6B),        R^(6C), R^(7B), R^(7C), R^(8B), R^(8C), R^(9B), R^(9C), R^(10B)        and R^(10C) substituents bonded to the same nitrogen atom may        optionally be joined to form a substituted or unsubstituted        heterocycloalkyl or substituted or unsubstituted heteroaryl; and    -   X^(1.1), X^(2.1), X^(3.1), X^(4.1), X^(5.1), X^(6.1), X^(7.1),        X^(8.1), X^(9.1) and X^(10.1) are independently —Cl, —Br, —I or        —F, wherein at least one of X¹, X² and X³ is N.

Embodiment P2

The method of embodiment P1, wherein the compound is:

or pharmaceutically acceptable salts thereof.

Embodiment P3

A method of treating a malignancy that is positive for Epstein BarrVirus (EBV), the method comprising administering to a subject in needthereof a therapeutically effective amount of a compound of formula(II):

or a pharmaceutically acceptable salt thereof,

wherein:

A is a substituted or unsubstituted heterocycloalkyl;

X¹ is CR⁸ or N;

X² is CR⁹ or N;

X³ is CR¹⁰ or N;

X⁴ is C, CR¹¹ or N;

z1 is an integer from 0 to 5;

z2 is an integer from 0 to 13;

z3 is an integer from 0 to 12;

z4 is an integer from 0 to 3;

is a single bond or double bond, wherein if

is a single bond, then X⁴ is CR¹¹ or N, and if

is a double bond, then X⁴ is C;

L⁷ is a bond, —O—, —S—, —NR^(7B)—, —C(O)—, —C(O)O—, —S(O)—, —S(O)₂—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, or substituted or unsubstituted heteroarylene;

R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1), —CN,—SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C),—ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), —NHC(O)NR^(1B)R^(1C),—N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D), —C(O)OR^(1D),—C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A), —NR^(1B)C(O)R^(1D),—NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃, —OCHX^(1.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R² is hydrogen, halogen, —CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN,—SO_(n2)R^(2A), —SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C),—ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C),—N(O)_(m2), —NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D),—C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D),—NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R³ is independently hydrogen, halogen, —CX^(3.1) ₃, —CHX^(3.1) ₂,—CH₂X^(3.1), —CN, —SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C),—NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C),—NHC(O)NR^(3B)R^(3C), —N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D),—C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A),—NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃,—OCHX^(3.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl;

R⁴ is hydrogen, halogen, —CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1), —CN,—SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C),—ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C),—N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D),—C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D),—NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl;

R⁵ is independently hydrogen, halogen, oxo, —CX^(5.1) ₃, —CHX^(5.1) ₂,—CH₂X^(5.1), —CN, —SO_(n5)R^(5A), —SO_(v5)NR^(5B)R^(5C),—NHNR^(5B)R^(5C), —ONR^(5B)R^(5C), —NHC(O)NHNR^(5B)R^(5C),—NHC(O)NR^(5B)R^(5C), —N(O)_(m5), —NR^(5B)R^(5C), —C(O)R^(5D),—C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A), —NR^(5B)SO₂R^(5A),—NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D), —NR^(5B)OR^(5D), —OCX^(5.1) ₃,—OCHX^(5.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl;

R⁶ is independently hydrogen, halogen, oxo, —CX^(6.1) ₃, —CHX^(6.1) ₂,—CH₂X^(6.1), —CN, —SO_(n6)R^(6A), —SO_(v6)NR^(6B)R^(6C),—NHNR^(6B)R^(6C), —ONR^(6B)R^(6C), —NHC(O)NHNR^(6B)R^(6C),—NHC(O)NR^(6B)R^(6C), —N(O)_(m6), —NR^(6B)R^(6C), —C(O)R^(6D),—C(O)OR^(6D), —C(O)NR^(6B)R^(6C), —OR^(6A), —NR^(6B)SO₂R^(6A),—NR^(6B)C(O)R^(6D), —NR^(6B)C(O)OR^(6D), —NR^(6B)OR^(6D), —OCX^(6.1) ₃,—OCHX^(6.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl;

R⁸ is hydrogen, halogen, —CX^(8.1) ₃, —CHX^(8.1) ₂, —CH₂X^(8.1), —CN,—SO_(n8)R^(8A), —SO_(v8)NR^(8B)R^(8C), —NHNR^(8B)R^(8C),—ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C), —NHC(O)NR^(8B)R^(8C),—N(O)_(m8), —NR^(8B)R^(8C), —C(O)R^(8D), —C(O)OR^(8D),—C(O)NR^(8B)R^(8C), —OR^(8A), —NR^(8B)SO₂R^(8A), —NR^(8B)C(O)R^(8D),—NR^(8B)C(O)OR^(8D), —NR^(8B)OR^(8D), —OCX^(8.1) ₃, —OCHX^(8.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R⁹ is hydrogen, halogen, —CX^(9.1) ₃, —CHX^(9.1) ₂, —CH₂X^(9.1), —CN,—SO_(n9)R^(9A), —SO_(v9)NR^(9B)R^(9C), —NHNR^(9B)R^(9C),—ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C), —NHC(O)NR^(9B)R^(9C),—N(O)_(m9), —NR^(9B)R^(9C), —C(O)R^(9D), —C(O)OR^(9D),—C(O)NR^(9B)R^(9C), —OR^(9A), —NR^(9B)SO₂R^(9A), —NR^(9B)C(O)R^(9D),—NR^(9B)C(O)OR^(9D), —NR^(9B)OR^(9D), —OCX^(9.1) ₃, —OCHX^(9.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R¹⁰ is hydrogen, halogen, —CX^(10.1) ₃, —CHX^(10.1) ₂, —CH₂X^(10.1),—CN, —SO_(n10)R^(10A), —SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C),—ONR^(10B)R^(10C), —NHC(O)NHNR^(10B)R^(10C), —NHC(O)NR^(10B)R^(10C),—N(O)_(m10), —NR^(10B)R^(10C), —C(O)R^(10D), —C(O)OR^(10D),—C(O)NR^(10B)R^(10C), —OR^(10A), —NR^(10B)SO₂R^(10A),—NR^(10B)C(O)R^(10D), —NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D),—OCX^(10.1) ₃, —OCHX^(10.1) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R¹¹ is hydrogen, halogen, —CX^(11.1) ₃, —CHX^(11.1) ₂, —CH₂X^(11.1),—CN, —SO_(n11)R^(11A), —SO_(v11)NR^(11B)R^(11C), —NHNR^(11B)R^(11C),—ONR^(11B)R^(11C), —NHC(O)NHNR^(11B)R^(11C), —NHC(O)NR^(11B)R^(11C),—N(O)_(m11), —NR^(11B)R^(11C), —C(O)R^(11D), —C(O)OR^(11D),—C(O)NR^(11B)R^(11C), —OR^(11A), —NR^(11B)SO₂R^(11A),—NR^(11B)C(O)R^(11D), —NR^(11B)C(O)OR^(11D), —NR^(11B)OR^(11D),—OCX^(11.1) ₃, —OCHX^(1.1) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A),R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D), R^(5A), R^(5B),R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D), R^(8A), R^(8B), R^(8C),R^(8D), R^(9A), R^(9B), R^(9C), R^(9D), R^(10A), R^(10B), R^(10C),R^(10D), R^(11A), R^(11B), R^(11C) and R^(11D) are independentlyhydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —COOH, —CONH₂, substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(1B) and R^(1C), R^(2B) and R^(2C), R^(3B)and R^(3C), R^(4B) and R^(4C), R^(5B) and R^(5C), R^(6B) and R^(6C),R^(8B) and R^(8C), R^(9B) and R^(9C), R^(10B) and R^(10C), R^(11B) andR^(11C) substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl;

n1, n2, n3, n4, n5, n6, n8, n9, n10 and n11 are independently an integerfrom 0 to 4;

m1, m2, m3, m4, m5, m6, m8, m9, m10, m11, v1, v2, v3, v4, v5, v6, v8,v9, v10, and v11 are independently 1 or 2; and

X^(1.1), X^(2.1), X^(3.1), X^(4.1), X^(5.1), X^(6.1), X^(8.1), X^(9.1),X^(10.1), and X^(11.1) are independently —Cl, —Br, —I or —F, wherein atleast one of X¹, X², and X³ is N.

Embodiment P4

The method of embodiment P3, wherein the compound is:

or pharmaceutically acceptable salts thereof.

Embodiment P5

A method of treating a malignancy that is positive for Epstein BarrVirus (EBV), the method comprising administering to a subject in needthereof a therapeutically effective amount of a compound of formula(III):

or a pharmaceutically acceptable salt thereof,

wherein:

A is substituted or unsubstituted cycloalkyl or substituted orunsubstituted heterocycloalkyl;

X¹ is CR⁸ or N;

X² is CR⁹ or N;

X³ is CR¹⁰ or N;

X⁴ is C, CR¹¹ or N;

X⁷ is NR⁷ or N, wherein when L⁷ is covalently bound to X⁷, then X⁷ is N;

n1, n2, n3, n4, n5, n6, n8, n9, n10, n11, and n17 are independently aninteger from 0 to 4;

m1, m2, m3, m4, m5, m6, m8, m9, m10, m11, m17, v1, v2, v3, v4, v5, v6,v8, v9, v10, v11, and v17 are independently 1 or 2;

z1 is an integer from 0 to 5;

z2 is an integer from 0 to 8;

z3 is an integer from 0 to 12;

is a single bond or double bond, wherein if

is a single bond, then X⁴ is CR¹¹ or N, and if

is a double bond, then X⁴ is C;

L⁷ is a bond, —O—, —S—, —NR^(7B)—, —C(O)—, —C(O)O—, —S(O)—, —S(O)₂—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, or substituted or unsubstituted heteroarylene;

R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1), —CN,—SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C),—ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), —NHC(O)NR^(1B)R^(1C),—N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D), —C(O)OR^(1D),—C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A), —NR^(1B)C(O)R^(1D),—NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃, —OCHX^(1.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R² is hydrogen, halogen, —CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN,—SO_(n2)R^(2A), —SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C),—ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C),—N(O)_(m2), —NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D),—C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D),—NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R³ is independently hydrogen, halogen, —CX^(3.1) ₃, —CHX^(3.1) ₂,—CH₂X^(3.1), —CN, —SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C),—NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C),—NHC(O)NR^(3B)R^(3C), —N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D),—C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A),—NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃,—OCHX^(3.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl;

R⁴ is hydrogen, halogen, —CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1), —CN,—SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C),—ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C),—N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D),—C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D),—NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl;

R⁵ is independently hydrogen, halogen, oxo, —CX^(5.1) ₃, —CHX^(5.1) ₂,—CH₂X^(5.1), —CN, —SO_(n5)R^(5A), —SO_(v5)NR^(5B)R^(5C),—NHNR^(5B)R^(5C), —ONR^(5B)R^(5C), —NHC(O)NHNR^(5B)R^(5C),—NHC(O)NR^(5B)R^(5C), —N(O)_(m5), —NR^(5B)R^(5C), —C(O)R^(5D),—C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A), —NR^(5B)SO₂R^(5A),—NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D), —NR^(5B)OR^(5D), —OCX^(5.1) ₃,—OCHX^(5.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl;

R⁶ is independently hydrogen, halogen, oxo, —CX^(6.1) ₃, —CHX^(6.1) ₂,—CH₂X^(6.1), —CN, —SO_(n6)R^(6A), —SO_(v6)NR^(6B)R^(6C),—NHNR^(6B)R^(6C), —ONR^(6B)R^(6C), —NHC(O)NHNR^(6B)R^(6C),—NHC(O)NR^(6B)R^(6C), —N(O)_(m6), —NR^(6B)R^(6C), —C(O)R^(6D),—C(O)OR^(6D), —C(O)NR^(6B)R^(6C), —OR^(6A), —NR^(6B)SO₂R^(6A),—NR^(6B)C(O)R^(6D), —NR^(6B)C(O)OR^(6D), —NR^(6B)OR^(6D), —OCX^(6.1) ₃,—OCHX^(6.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl;

R⁸ is hydrogen, halogen, —CX^(8.1) ₃, —CHX^(8.1) ₂, —CH₂X^(8.1), —CN,—SO_(n8)R^(8A), —SO_(v8)NR^(8B)R^(8C), —NHNR^(8B)R^(8C),—ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C), —NHC(O)NR^(8B)R^(8C),—N(O)_(m8), —NR^(8B)R^(8C), —C(O)R^(8D), —C(O)OR^(8D),—C(O)NR^(8B)R^(8C), —OR^(8A), —NR^(8B)SO₂R^(8A), —NR^(8B)C(O)R^(8D),—NR^(8B)C(O)OR^(8D), —NR^(8B)OR^(8D), —OCX^(8.1) ₃, —OCHX^(8.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R⁹ is hydrogen, halogen, —CX^(9.1) ₃, —CHX^(9.1) ₂, —CH₂X^(9.1), —CN,—SO_(n9)R^(9A), —SO_(v9)NR^(9B)R^(9C), —NHNR^(9B)R^(9C),—ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C), —NHC(O)NR^(9B)R^(9C),—N(O)_(m9), —NR^(9B)R^(9C), —C(O)R^(9D), —C(O)OR^(9D),—C(O)NR^(9B)R^(9C), —OR^(9A), —NR^(9B)SO₂R^(9A), —NR^(9B)C(O)R^(9D),—NR^(9B)C(O)OR^(9D), —NR^(9B)OR^(9D), —OCX^(9.1) ₃, —OCHX^(9.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R¹⁰ is hydrogen, halogen, —CX^(10.1) ₃, —CHX^(10.1) ₂, —CH₂X^(10.1),—CN, —SO_(n10)R^(10A), —SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C),—ONR^(10B)R^(10C), —NHC(O)NHNR^(10B)R^(10C), —NHC(O)NR^(10B)R^(10C),—N(O)_(m10), —NR^(10B)R^(10C), —C(O)R^(10D), —C(O)OR^(10D),—C(O)NR^(10B)R^(10C), —OR^(10A), —NR^(10B)SO₂R^(10A),—NR^(10B)C(O)R^(10D), —NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D),—OCX^(10.1) ₃, —OCHX^(10.1) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R¹¹ is hydrogen, halogen, —CX^(11.1) ₃, —CHX^(11.1) ₂, —CH₂X^(11.1),—CN, —SO_(n11)R^(11A), —SO_(v11)NR^(11B)R^(11C), —NHNR^(11B)R^(11C),—ONR^(11B)R^(11C), —NHC(O)NHNR^(11B)R^(11C), —NHC(O)NR^(11B)R^(11C),—N(O)_(m11), —NR^(11B)R^(11C), —C(O)R^(11D), —C(O)OR^(11D),—C(O)NR^(11B)R^(11C), —OR^(11A), —NR^(11B)SO₂R^(11A),—NR^(11B)C(O)R^(11D), —NR^(11B)C(O)OR^(11D), —NR^(11B)OR^(11D),—OCX^(11.1) ₃, —OCHX^(11.1) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R¹⁷ is hydrogen, halogen, —CX^(17.1) ₃, —CHX^(17.1) ₂, —CH₂X^(17.1),—CN, —SO_(n17)R^(17A), —SO_(v17)NR^(17B)R^(17C), —NHNR^(17B)R^(17C),—ONR^(17B)R^(17C), —NHC(O)NHNR^(17B)R^(17C), —NHC(O)NR^(17B)R^(17C),—N(O)_(m17), —NR^(17B)R^(17C), —C(O)R^(17D), —C(O)OR^(17D),—C(O)NR^(17B)R^(17C), —OR^(17A), —NR^(17B)SO₂R^(17A),—NR^(17B)C(O)R^(17D), —NR^(17B)C(O)OR^(17D), —NR^(17B)OR^(17D),—OCX^(17.1) ₃, —OCHX^(1.1) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A),R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D), R^(5A), R^(5B),R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D), R^(8A), R^(8B), R^(8C),R^(8D), R^(9A), R^(9B), R^(9C), R^(9D), R^(10A), R^(10B), R^(10C),R^(10D), R^(11A), R^(11B), R^(11C), R^(11D) R^(17A), R^(17B), R^(17C)and R^(17D) are independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃,—CI₃, —COOH, —CONH₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R^(1B)and R^(1C), R^(2B) and R^(2C), R^(3B) and R^(3C), R^(4B) and R^(4C),R^(5B) and R^(5C), R^(6B) and R^(6C), R^(8B) and R^(8C), R^(9B) andR^(9C), R^(10B) and R^(10C) R^(11B) and R^(11C) and R^(17B) and R^(17C)substituents bonded to the same nitrogen atom may optionally be joinedto form a substituted or unsubstituted heterocycloalkyl or substitutedor unsubstituted heteroaryl; and

X^(1.1), X^(2.1), X^(3.1), X^(4.1), X^(5.1), X^(6.1), X^(8.1), X^(9.1),X^(10.1), X^(11.1) and X^(17.1) are independently —Cl, —Br, —I or —F,wherein at least one of X¹, X² and X³ is N.

Embodiment P6

The method of embodiment P5, wherein the compound is:

or pharmaceutically acceptable salts thereof.

Embodiment P7

The method of any one of embodiments P1 to P6, wherein the EBV positivemalignancy is Burkitt lymphoma, Hodgkin's lymphoma, diffuse large B-celllymphoma, NK/T-cell lymphoma, cutaneous T-cell lymphoma, nasopharyngealcarcinoma, gastric cancer, vulvar squamous cell carcinoma, salivarygland cancer, orbit choroidal melanoma, or adenocarcinoma consistentwith pancreaticobiliary.

Embodiment P8

The method of embodiment P7 further comprising co-administering to asubject in need thereof a chemotherapeutic agent or anticancer agent.

Embodiment P9

The method of embodiment P8, wherein the chemotherapeutic agent oranticancer agent is an antiproliferative/antineoplastic drug, anantimetabolite, an antitumor antibiotic, an antimitotic agent, atopoisomerase inhibitor, a cytostatic agent, an estrogen receptor downregulator, an antiandrogen, a LHRH antagonist or LHRH agonist, aprogestogen, an aromatase inhibitor, an inhibitor of 5-alpha-reductase,an agent which inhibits cancer cell invasion, an inhibitor of growthfactor function, a farnesyl transferase inhibitor, a tyrosine kinaseinhibitor, a serine/threonine kinase inhibitor, an inhibitor of theepidermal growth factor family, an inhibitor of the platelet-derivedgrowth factor family, an inhibitor of the hepatocyte growth factorfamily; an antiangiogenic agent, a vascular damaging agent, an antisensetherapy agent, an anti-ras antisense agent, an gene therapy agent, animmunotherapeutic agent, or an antibody.

Embodiment P10

The method of embodiment P9, wherein the chemotherapeutic agent oranticancer agent is an anti-proliferative agent, a chemotherapeuticagent, an antimetabolite, an antimicrotubule agent, an alkylating agent,a platinum agent, an anthracycline, an antitumor antibiotic, atopoisomerase inhibitor, a purine antagonist, a pyrimidine antagonist, acell maturing agent, a DNA repair enzyme inhibitor, an enzyme thatprevents cell survival, a histone deacetylase inhibitor, a cytotoxicagent, a hormone, an antibody, an immuno-modulator, a Bcr-Abl kinaseinhibitor, a hormone agonist or antagonist, partial agonist or partialantagonist, a kinase inhibitor, surgery, radiotherapy, an endocrinetherapy, a biological response modifier, a hyperthermial agent, acryotherapeutic agent, an immuomodulating agent, an agent to attenuateany adverse effects, a spindle poison, a podophyllotoxin, an antibiotic,or a nitrosourea.

Embodiment P11

The method of embodiment P10, wherein the antimetabolite is 5-fluorouracil, methotrexate, azacitidine, decitabine, fludarabine orcytarabine.

Embodiment P12

The method of embodiment P10, wherein the antimicrotubule agent is avinca alkaloid or a taxane.

Embodiment P13

The method of embodiment P10, wherein the alkylating agent ismechlorethamine, chlorambucil, cyclophosphamide, melphalan, carmustine,lomustine, ifosfamide, carmustine, busulfan, cyclophosphamide,dacarbazine, ifosfamide, bischloroethylnitrosurea or hydroxyurea.

Embodiment P14

The method of embodiment P10, wherein the platinum agent is cisplatin,carboplatin, oxaliplatin, satraplatin (JM-216) or CI-973.

Embodiment P15

The method of embodiment P9, wherein the chemotherapeutic agent oranticancer agent is an antibody.

Embodiment P16

The method of embodiment P9, wherein the chemotherapeutic agent oranticancer agent is an immunomodulating agent.

Embodiment P17

Use of the compound of any one of embodiment P1 to P6 to treat amalignancy that is positive for Epstein Barr Virus (EBV).

Embodiment P18

Use of the compound of any one of embodiment P1 to P6 in the manufactureof a medicament to treat a malignancy that is positive for Epstein BarrVirus (EBV).

FURTHER EMBODIMENTS Embodiment 1

A method of treating a malignancy that is positive for Epstein BarrVirus (EBV), the method comprising administering to a subject in needthereof a therapeutically effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X¹ is CR⁸ or N;    -   X² is CR⁹ or N;    -   X³ is CR¹⁰ or N;    -   n1, n2, n3, n4, n5, n6, n7, n8, n9 and n10 are independently an        integer from 0 to 4;    -   m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, v1, v2, v3, v4, v5, v6,        v7, v8, v9 and v10 are independently 1 or 2;    -   z1 is an integer from 0 to 5;    -   z2 is an integer from 0 to 2;    -   z3 is an integer from 0 to 11;    -   z4 is an integer from 0 to 2;    -   L⁷ is a bond, —O—, —S—, —NR^(7.2B)—, —C(O)—, —C(O)O—, —S(O)—,        —S(O)₂—, substituted or unsubstituted alkylene, substituted or        unsubstituted heteroalkylene, substituted or unsubstituted        cycloalkylene, substituted or unsubstituted heterocycloalkylene,        substituted or unsubstituted arylene, or substituted or        unsubstituted heteroarylene;    -   R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1),        —CN, —N₃, —SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C),        —NHNR^(1B)R^(1C), —ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C),        —NHC(O)NR^(1B)R^(1C), —N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D),        —C(O)OR^(1D), —C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A),        —NR^(1B)C(O)R^(1D), —NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D),        —OCX^(1.1) ₃, —OCHX^(1.1) ₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R² is hydrogen, halogen, —CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1),        —CN, —N₃, —SO_(n2)R^(2A), —SO_(v2)NR^(2B)R^(2C),        —NHNR^(2B)R^(2C), —ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C),        —NHC(O)NR^(2B)R^(2C), —N(O)_(m2), —NR^(2B)R^(2C), —C(O)R^(2D),        —C(O)OR^(2D), —C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A),        —NR^(2B)C(O)R^(2D), —NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D),        —OCX^(2.1) ₃, —OCHX^(2.1) ₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R³ is independently hydrogen, halogen, —CX^(3.1) ₃, —CHX^(3.1)        ₂, —CH₂X^(3.1), —CN, —N₃, —SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C),        —NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C),        —NHC(O)NR^(3B)R^(3C), —N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D),        —C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A),        —NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D),        —OCX^(3.1) ₃, —OCHX^(3.1) ₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl or        substituted or unsubstituted heteroaryl;    -   R⁴ is hydrogen, halogen, —CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1),        —CN, —N₃, —SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C),        —NHNR^(4B)R^(4C), —ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C),        —NHC(O)NR^(4B)R^(4C), —N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D),        —C(O)OR^(4D), —C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A),        —NR^(4B)C(O)R^(4D), —NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D),        —OCX^(4.1) ₃, —OCHX^(4.1) ₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl or        substituted or unsubstituted heteroaryl;    -   R⁵ is independently hydrogen, halogen, oxo, —CX^(5.1) ₃,        —CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —N₃, —SO_(n5)R^(5A),        —SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), —ONR^(5B)R^(5C),        —NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C), —N(O)_(m5),        —NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D), —C(O)NR^(5B)R^(5C),        —OR^(5A), —NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D),        —NR^(5B)C(O)OR^(5D), —NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1)        ₂, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   R⁶ is independently hydrogen, halogen, oxo, —CX^(6.1) ₃,        —CHX^(6.1) ₂, —CH₂X^(6.1), —CN, —N₃, —SO_(n6)R^(6A),        —SO_(v6)NR^(6B)R^(6C), —NHNR^(6B)R^(6C), —ONR^(6B)R^(6C),        —NHC(O)NHNR^(6B)R^(6C), —NHC(O)NR^(6B)R^(6C), —N(O)_(m6),        —NR^(6B)R^(6C), —C(O)R^(6D), —C(O)OR^(6D), —C(O)NR^(6B)R^(6C),        —OR^(6A), —NR^(6B)SO₂R^(6A), —NR^(6B)C(O)R^(6D),        —NR^(6B)C(O)OR^(6D), —NR^(6B)OR^(6D), —OCX^(6.1) ₃, —OCHX^(6.1)        ₂, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   R⁷ is hydrogen, halogen, —CX^(7.1) ₃, —CHX^(7.1) ₂, —CH₂X^(7.1),        —CN, —N₃, —SO_(n7)R^(7A), —SO_(v7)NR^(7B)R^(7C),        —NHNR^(7B)R^(7C), —ONR^(7B)R^(7C), —NHC(O)NHNR^(7B)R^(7C),        —NHC(O)NR^(7B)R^(7C), —N(O)_(m7), —NR^(7B)R^(7C), —C(O)R^(7D),        —C(O)OR^(7D), —C(O)NR^(7B)R^(7C), —OR^(7A), —NR^(7B)SO₂R^(7A),        —NR^(7B)C(O)R^(7D), —NR^(7B)C(O)OR^(7D), —NR^(7B)OR^(7D),        —OCX^(7.1) ₃, —OCHX^(7.1) ₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl or        substituted or unsubstituted heteroaryl;    -   R⁸ is hydrogen, halogen, —CX^(8.1) ₃, —CHX^(8.1) ₂, —CH₂X^(8.1),        —CN, —N₃, —SO_(n8)R^(8A), —SO_(v8)NR^(8B)R^(8C),        —NHNR^(8B)R^(8C), —ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C),        —NHC(O)NR^(8B)R^(8C), —N(O)_(m8), —NR^(8B)R^(8C), —C(O)R^(8D),        —C(O)OR^(8D), —C(O)NR^(8B)R^(8C), —OR^(8A), —NR^(8B)SO₂R^(8A),        —NR^(8B)C(O)R^(8D), —NR^(8B)C(O)OR^(8D), —NR^(8B)OR^(8D),        —OCX^(8.1) ₃, —OCHX^(8.1) ₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R⁹ is hydrogen, halogen, —CX^(9.1) ₃, —CHX^(9.1) ₂, —CH₂X^(9.1),        —CN, —N₃, —SO_(n9)R^(9A), —SO_(v9)NR^(9B)R^(9C),        —NHNR^(9B)R^(9C), —ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C),        —NHC(O)NR^(9B)R^(9C), —N(O)_(m9), —NR^(9B)R^(9C), —C(O)R^(9D),        —C(O)OR^(9D), —C(O)NR^(9B)R^(9C), —OR^(9A), —NR^(9B)SO₂R^(9A),        —NR^(9B)C(O)R^(9D), —NR^(9B)C(O)OR^(9D), —NR^(9B)OR^(9D),        —OCX^(9.1) ₃, —OCHX^(9.1) ₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R¹⁰ is hydrogen, halogen, —CX^(10.1) ₃, —CHX^(10.1) ₂,        —CH₂X^(10.1), —CN, —N₃, —SO_(n10)R^(10A),        —SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C), —ONR^(10B)R^(10C),        —NHC(O)NHNR^(10B)R^(10C), —NHC(O)NR^(10B)R^(10C), —N(O)_(m10),        —NR^(10B)R^(10C), —C(O)R^(10D), —C(O)OR^(10D),        —C(O)NR^(10B)R^(10C), —OR^(10A), —NR^(10B)SO₂R^(10A),        —NR^(10B)C(O)R^(10D), —NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D),        —OCX^(10.1) ₃, —OCHX^(10.1) ₂, substituted or unsubstituted        alkyl, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D),        R^(3A), R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D),        R^(5A), R^(5B), R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D),        R^(7A), R^(7B), R^(7C), R^(7D), R^(8A), R^(8B), R^(8C), R^(8D),        R^(9A), R^(9B), R^(9C), R^(9D), R^(10A), R^(10B), R^(10C) and        R^(10D) are independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃,        —CI₃, —COOH, —CONH₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R^(1B), R^(1C), R^(2B), R^(2C), R^(3B), R^(3C), R^(4B), R^(4C),        R^(5B), R^(5C), R^(6B), R^(6C), R^(7B), R^(7C), R^(8B), R^(8C),        R^(9B), R^(9C), R^(10B) and R^(10C) substituents bonded to the        same nitrogen atom may optionally be joined to form a        substituted or unsubstituted heterocycloalkyl or substituted or        unsubstituted heteroaryl; and X^(1.1), X^(2.1), X^(3.1),        X^(4.1), X^(5.1), X^(6.1), X^(7.1), X^(8.1), X^(9.1) and        X^(10.1) are independently —Cl, —Br, —I or —F, wherein at least        one of X¹, X² and X³ is N.

Embodiment 2

The method of embodiment 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

Embodiment 3

A method of treating a malignancy that is positive for Epstein BarrVirus (EBV), the method comprising administering to a subject in needthereof a therapeutically effective amount of a compound of formula(II):

or a pharmaceutically acceptable salt thereof,

wherein:

A is a substituted or unsubstituted heterocycloalkyl;

X¹ is CR⁸ or N;

X² is CR⁹ or N;

X³ is CR¹⁰ or N;

X⁴ is C, CR¹¹ or N;

z1 is an integer from 0 to 5;

z2 is an integer from 0 to 13;

z3 is an integer from 0 to 12;

z4 is an integer from 0 to 3;

is a single bond or double bond, wherein if

is a single bond, then X⁴ is CR¹¹ or N, and if

is a double bond, then X⁴ is C;

L⁷ is a bond, —O—, —S—, —NR^(7B)—, —C(O)—, —C(O)O—, —S(O)—, —S(O)₂—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, or substituted or unsubstituted heteroarylene;

R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1), —CN,—SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C),—ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), —NHC(O)NR^(1B)R^(1C),—N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D), —C(O)OR^(1D),—C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A), —NR^(1B)C(O)R^(1D),—NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃, —OCHX^(1.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R² is hydrogen, halogen, —CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN,—SO_(n2)R^(2A), —SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C),—ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C),—N(O)_(m2), —NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D),—C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D),—NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R³ is independently hydrogen, halogen, —CX^(3.1) ₃, —CHX^(3.1) ₂,—CH₂X^(3.1), —CN, —SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C),—NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C),—NHC(O)NR^(3B)R^(3C), —N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D),—C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A),—NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃,—OCHX^(3.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl;

R⁴ is hydrogen, halogen, —CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1), —CN,—SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C),—ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C),—N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D),—C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D),—NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl;

R⁵ is independently hydrogen, halogen, oxo, —CX^(5.1) ₃, —CHX^(5.1) ₂,—CH₂X^(5.1), —CN, —SO_(n5)R^(5A), —SO_(v5)NR^(5B)R^(5C),—NHNR^(5B)R^(5C), —NR^(5B)R^(5C), —ONR^(5B)R^(5C),—NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C), —N(O)_(m5),—NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A),—NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D),—NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl;

R⁶ is independently hydrogen, halogen, oxo, —CX^(6.1) ₃, —CHX^(6.1) ₂,—CH₂X^(6.1), —CN, —SO_(n6)R^(6A), —SO_(v6)NR^(6B)R^(6C),—NHNR^(6B)R^(6C), —ONR^(6B)R^(6C), —NHC(O)NHNR^(6B)R^(6C),—NHC(O)NR^(6B)R^(6C), —N(O)_(m6), —NR^(6B)R^(6C), —C(O)R^(6D),—C(O)OR^(6D), —C(O)NR^(6B)R^(6C), —OR^(6A), —NR^(6B)SO₂R^(6A),—NR^(6B)C(O)R^(6D), —NR^(6B)C(O)OR^(6D), —NR^(6B)OR^(6D), —OCX^(6.1) ₃,—OCHX^(6.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl;

R⁸ is hydrogen, halogen, —CX^(8.1) ₃, —CHX^(8.1) ₂, —CH₂X^(8.1), —CN,—SO_(n8)R^(8A), —SO_(v8)NR^(8B)R^(8C), —NHNR^(8B)R^(8C),—ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C), —NHC(O)NR^(8B)R^(8C),—N(O)_(m8), —NR^(8B)R^(8C), —C(O)R^(8D), —C(O)OR^(8D),—C(O)NR^(8B)R^(8C), —OR^(8A), —NR^(8B)SO₂R^(8A), —NR^(8B)C(O)R^(8D),—NR^(8B)C(O)OR^(8D), —NR^(8B)OR^(8D), —OCX^(8.1) ₃, —OCHX^(8.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R⁹ is hydrogen, halogen, —CX^(9.1) ₃, —CHX^(9.1) ₂, —CH₂X^(9.1), —CN,—SO_(n9)R^(9A), —SO_(v9)NR^(9B)R^(9C), —NHNR^(9B)R^(9C),—ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C), —NHC(O)NR^(9B)R^(9C),—N(O)_(m9), —NR^(9B)R^(9C), —C(O)R^(9D), —C(O)OR^(9D),—C(O)NR^(9B)R^(9C), —OR^(9A), —NR^(9B)SO₂R^(9A), —NR^(9B)C(O)R^(9D),—NR^(9B)C(O)OR^(9D), —NR^(9B)OR^(9D), —OCX^(9.1) ₃, —OCHX^(9.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R¹⁰ is hydrogen, halogen, —CX^(10.1) ₃, —CHX^(10.1) ₂, —CH₂X^(10.1),—CN, —SO_(n10)R^(10A), —SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C),—ONR^(10B)R^(10C), —NHC(O)NHNR^(10B)R^(10C), —NHC(O)NR^(10B)R^(10C),—N(O)_(m10), —NR^(10B)R^(10C), —C(O)R^(10D), —C(O)OR^(10D),—C(O)NR^(10B)R^(10C), —OR^(10A), —NR^(10B)SO₂R^(10A),—NR^(10B)C(O)R^(10D), —NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D),—OCX^(10.1) ₃, —OCHX^(10.1) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R¹¹ is hydrogen, halogen, —CX^(11.1) ₃, —CHX^(11.1) ₂, —CH₂X^(11.1),—CN, —SO_(n11)R^(11A), —SO_(v11)NR^(11B)R^(11C), —NHNR^(11B)R^(11C),—ONR^(11B)R^(11C), —NHC(O)NHNR^(11B)R^(11C), —NHC(O)NR^(11B)R^(11C),—N(O)_(m11), —NR^(11B)R^(11C), —C(O)R^(11D), —C(O)OR^(11D),—C(O)NR^(11B)R^(11C), —OR^(11A), —NR^(11B)SO₂R^(11A),—NR^(11B)C(O)R^(11D), —NR^(11B)C(O)OR^(11D), —NR^(11B)OR^(11D),—OCX^(11.1) ₃, —OCHX^(11.1) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A),R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D), R^(5A), R^(5B),R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D), R^(8A), R^(8B), R^(8C),R^(8D), R^(9A), R^(9B), R^(9C), R^(9D), R^(10A), R^(10B), R^(10C),R^(10D), R^(11A), R^(11B), R^(11C) and R^(11D) are independentlyhydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —COOH, —CONH₂, substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(1B) and R^(1C), R^(2B) and R^(2C), R^(3B)and R^(3C), R^(4B) and R^(4C), R^(5B) and R^(5C), R^(6B) and R^(6C),R^(8B) and R^(8C), R^(9B) and R^(9C), R^(10B) and R^(10C), R^(11B) andR^(11C) substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl;

n1, n2, n3, n4, n5, n6, n8, n9, n10 and n11 are independently an integerfrom 0 to 4;

m1, m2, m3, m4, m5, m6, m8, m9, m10, m11, v1, v2, v3, v4, v5, v6, v8,v9, v10, and v11 are independently 1 or 2; and

X^(1.1), X^(2.1), X^(3.1), X^(4.1), X^(5.1), X^(6.1), X^(8.1), X^(9.1),X^(10.1), and X^(11.1) are independently —Cl, —Br, —I or —F, wherein atleast one of X¹, X², and X³ is N.

Embodiment 4

The method of embodiment 3, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

Embodiment 5

A method of treating a malignancy that is positive for Epstein BarrVirus (EBV), the method comprising administering to a subject in needthereof a therapeutically effective amount of a compound of formula(III):

or a pharmaceutically acceptable salt thereof,

wherein:

A is substituted or unsubstituted cycloalkyl or substituted orunsubstituted heterocycloalkyl;

X¹ is CR⁸ or N;

X² is CR⁹ or N;

X³ is CR¹⁰ or N;

X⁴ is C, CR¹¹ or N;

X⁷ is NR¹⁷ or N, wherein when L⁷ is covalently bound to X⁷, then X⁷ isN;

n1, n2, n3, n4, n5, n6, n8, n9, n10, n11, and n17 are independently aninteger from 0 to 4;

m1, m2, m3, m4, m5, m6, m8, m9, m10, m11, m17, v1, v2, v3, v4, v5, v6,v8, v9, v10, v11, and v17 are independently 1 or 2;

z1 is an integer from 0 to 5;

z2 is an integer from 0 to 8;

z3 is an integer from 0 to 12;

is a single bond or double bond, wherein if

is a single bond, then X⁴ is CR¹¹ or N, and if

is a double bond, then X⁴ is C;

L⁷ is a bond, —O—, —S—, —NR^(7B)—, —C(O)—, —C(O)O—, —S(O)—, —S(O)₂—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, or substituted or unsubstituted heteroarylene;

R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1), —CN,—SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C),—ONR^(10B)R^(10C), —NHC(O)NHNR^(1B)R^(1C), —NHC(O)NR^(1B)R^(1C),—N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D), —C(O)OR^(1D),—C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A), —NR^(1B)C(O)R^(1D),—NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃, —OCHX^(1.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R² is hydrogen, halogen, —CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN,—SO_(n2)R^(2A), —SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C),—ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C),—N(O)_(m2), —NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D),—C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D),—NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R³ is independently hydrogen, halogen, —CX^(3.1) ₃, —CHX^(3.1) ₂,—CH₂X^(3.1), —CN, —SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C),—NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C),—NHC(O)NR^(3B)R^(3C), —N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D),—C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A),—NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃,—OCHX^(3.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl;

R⁴ is hydrogen, halogen, —CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1), —CN,—SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C),—ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C),—N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D),—C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D),—NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl;

R⁵ is independently hydrogen, halogen, oxo, —CX^(5.1) ₃, —CHX^(5.1) ₂,—CH₂X^(5.1), —CN, —SO_(n5)R^(5A), —SO_(v5)NR^(5B)R^(5C),—NHNR^(5B)R^(5C), —ONR^(5B)R^(5C), —NHC(O)NHNR^(5B)R^(5C),—NHC(O)NR^(5B)R^(5C), —N(O)_(m5), —NR^(5B)R^(5C), —C(O)R^(5D),—C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A), —NR^(5B)SO₂R^(5A),—NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D), —NR^(5B)OR^(5D), —OCX^(5.1) ₃,—OCHX^(5.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl;

R⁶ is independently hydrogen, halogen, oxo, —CX^(6.1) ₃, —CHX^(6.1) ₂,—CH₂X^(6.1), —CN, —SO_(n6)R^(6A), —SO_(v6)NR^(6B)R^(6C),—NHNR^(6B)R^(6C), —ONR^(6B)R^(6C), —NHC(O)NHNR^(6B)R^(6C),—NHC(O)NR^(6B)R^(6C), —N(O)_(m6), —NR^(6B)R^(6C), —C(O)R^(6D),—C(O)OR^(6D), —C(O)NR^(6B)R^(6C), —OR^(6A), —NR^(6B)SO₂R^(6A),—NR^(6B)C(O)R^(6D), —NR^(6B)C(O)OR^(6D), —NR^(6B)OR^(6D), —OCX^(6.1) ₃,—OCHX^(6.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl;

R⁸ is hydrogen, halogen, —CX^(8.1) ₃, —CHX^(8.1) ₂, —CH₂X^(8.1), —CN,—SO_(n8)R^(8A), —SO_(v8)NR^(8B)R^(8C), —NHNR^(8B)R^(8C),—ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C), —NHC(O)NR^(8B)R^(8C),—N(O)_(m8), —NR^(8B)R^(8C), —C(O)R^(8D), —C(O)OR^(8D),—C(O)NR^(8B)R^(8C), —OR^(8A), —NR^(8B)SO₂R^(8A), —NR^(8B)C(O)R^(8D),—NR^(8B)C(O)OR^(8D), —NR^(8B)OR^(8D), —OCX^(8.1) ₃, —OCHX^(8.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R⁹ is hydrogen, halogen, —CX^(9.1) ₃, —CHX^(9.1) ₂, —CH₂X^(9.1), —CN,—SO_(n9)R^(9A), —SO_(v9)NR^(9B)R^(9C), —NHNR^(9B)R^(9C),—ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C), —NHC(O)NR^(9B)R^(9C),—N(O)_(m9), —NR^(9B)R^(9C), —C(O)R^(9D), —C(O)OR^(9D),—C(O)NR^(9B)R^(9C), —OR^(9A), —NR^(9B)SO₂R^(9A), —NR^(9B)C(O)R^(9D),—NR^(9B)C(O)OR^(9D), —NR^(9B)OR^(9D), —OCX^(9.1) ₃, —OCHX^(9.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R¹⁰ is hydrogen, halogen, —CX^(10.1) ₃, —CHX^(10.1) ₂, —CH₂X^(10.1),—CN, —SO_(n10)R^(10A), —SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C),—ONR^(10B)R^(10C), —NHC(O)NHNR^(10B)R^(10C), —NHC(O)NR^(10B)R^(10C),—N(O)_(m10), —NR^(10B)R^(10C), —C(O)R^(10D), —C(O)OR^(10D),—C(O)NR^(10B)R^(10C), —OR^(10A), —NR^(10B)SO₂R^(10A),—NR^(10B)C(O)R^(10D), —NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D),—OCX^(10.1) ₃, —OCHX^(10.1) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R¹¹ is hydrogen, halogen, —CX^(11.1) ₃, —CHX^(11.1) ₂, —CH₂X^(11.1),—CN, —SO_(n11)R^(11A), —SO_(v11)NR^(11B)R^(11C), —NHNR^(11B)R^(11C),—ONR^(11B)R^(11C), —NHC(O)NHNR^(11B)R^(11C), —NHC(O)NR^(11B)R^(11C),—N(O)_(m11), —NR^(11B)R^(11C), —C(O)R^(11D), —C(O)OR^(11D),—C(O)NR^(11B)R^(11C), —OR^(11A), —NR^(11B)SO₂R^(11A),—NR^(11B)C(O)R^(11D), —NR^(11B)C(O)OR^(11D), —NR^(11B)OR^(11D),—OCX^(11.1) ₃, —OCHX^(11.1) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R¹⁷ is hydrogen, halogen, —CX^(17.1) ₃, —CHX^(17.1) ₂, —CH₂X^(17.1),—CN, —SO_(n17)R^(17A), —SO_(v17)NR^(17B)R^(17C), —NHNR^(17B)R^(17C),—ONR^(17B)R^(17C), —NHC(O)NHNR^(17B)R^(17C), —NHC(O)NR^(17B)R^(17C),—N(O)_(m17), —NR^(17B)R^(17C), —C(O)R^(17D), —C(O)OR^(17D),—C(O)NR^(17B)R^(17C), —OR^(17A), —NR^(17B)SO₂R^(17A),—NR^(17B)C(O)R^(17D), —NR^(17B)C(O)OR^(17D), —NR^(17B)OR^(17D),—OCX^(17.1) ₃, —OCHX^(1.1) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A),R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D), R^(5A), R^(5B),R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D), R^(8A), R^(8B), R^(8C),R^(8D), R^(9A), R^(9B), R^(9C), R^(9D), R^(10A), R^(10B), R^(10C),R^(10D), R^(11A), R^(11B), R^(11C), R^(11D) R^(17A), R^(17B), R^(17C)and R^(17D) are independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃,—CI₃, —COOH, —CONH₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R^(1B)and R^(1C), R^(2B) and R^(2C), R^(3B) and R^(3C), R^(4B) and R^(4C),R^(5B) and R^(5C), R^(6B) and R^(6C), R^(8B) and R^(8C), R^(9B) andR^(9C), R^(10B) and R^(10C) R^(11B) and R^(11C) and R^(17B) and R^(17C)substituents bonded to the same nitrogen atom may optionally be joinedto form a substituted or unsubstituted heterocycloalkyl or substitutedor unsubstituted heteroaryl; and

X^(1.1), X^(2.1), X^(3.1), X^(4.1), X^(5.1), X^(6.1), X^(8.1), X^(9.1),X^(10.1), X^(11.1) and X^(17.1) are independently —Cl, —Br, —I or —F,wherein at least one of X¹, X² and X³ is N.

Embodiment 6

The method of embodiment 5, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

Embodiment 7

A method of treating a malignancy that is positive for Epstein BarrVirus (EBV), the method comprising administering to a subject in needthereof a therapeutically effective amount of a compound of formula(IV):

or a pharmaceutically acceptable salt thereof,wherein:

-   -   X¹ is CR⁸ or N;    -   X² is CR⁹ or N;    -   X³ is CR¹⁰ or N;    -   n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, and n44 are        independently an integer from 0 to 4;    -   m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, v1, v2, v3, v4, v5, v6,        v7, v8, v9, v10, and v44 are independently 1 or 2;    -   z1 is an integer from 0 to 5;    -   z2 is an integer from 0 to 4;    -   z3 is an integer from 0 to 11;    -   z4 is an integer from 0 to 2;    -   L⁷ is a bond, —O—, —S—, —NR^(7.2B)—, —C(O)—, —C(O)O—, —S(O)—,        —S(O)₂—, substituted or unsubstituted alkylene, substituted or        unsubstituted heteroalkylene, substituted or unsubstituted        cycloalkylene, substituted or unsubstituted heterocycloalkylene,        substituted or unsubstituted arylene, or substituted or        unsubstituted heteroarylene;    -   R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1),        —CN, —N₃, —SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C),        —NHNR^(1B)R^(1C), —ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C),        —NHC(O)NR^(1B)R^(1C), —N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D),        —C(O)OR^(1D), —C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A),        —NR^(1B)C(O)R^(1D), —NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D),        —OCX^(1.1) ₃, —OCHX^(1.1) ₂, —OCH₂X^(1.1), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R² is hydrogen, halogen, —CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1),        —CN, —N₃, —SO_(n2)R^(2A), —SO_(v2)NR^(2B)R^(2C),        —NHNR^(2B)R^(2C), —ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C),        —NHC(O)NR^(2B)R², —N(O)_(m2), —NR^(2B)R^(2C), —C(O)R^(2D),        —C(O)OR^(2D), —C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A),        —NR^(2B)C(O)R^(2D), —NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D),        —OCX^(2.1) ₃, —OCHX^(2.1) ₂, —OCH₂X^(2.1), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R³ is independently halogen, —CX^(3.1) ₃, —CHX^(3.1) ₂,        —CH₂X^(3.1), —CN, —N₃, —SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C),        —NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C),        —NHC(O)NR^(3B)R^(3C), —N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D),        —C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A),        —NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D),        —OCX^(3.1) ₃, —OCHX^(3.1) ₂, —OCH₂X^(3.1), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl or substituted or unsubstituted heteroaryl;    -   R⁴ is hydrogen, halogen, —CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1),        —CN, —N₃, —SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C),        —NHNR^(4B)R^(4C), —ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C),        —NHC(O)NR^(4B)R^(4C), —N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D),        —C(O)OR^(4D), —C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A),        —NR^(4B)C(O)R^(4D), —NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D),        —OCX^(4.1) ₃, —OCHX^(4.1) ₂, —OCH₂X^(4.1), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl or substituted or unsubstituted heteroaryl, or when X² is        CR⁹, then R⁴ and R⁹ may optionally be joined to form a        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R⁵ is independently halogen, oxo, —CX^(5.1) ₃, —CHX^(5.1) ₂,        —CH₂X^(5.1), —CN, —N₃, —SO_(n5)R^(5A), —SO_(v5)NR^(5B)R^(5C),        —NHNR^(5B)R^(5C), —ONR^(5B)R^(5C), —NHC(O)NHNR^(5B)R^(5C),        —NHC(O)NR^(5B)R^(5C), —N(O)_(m5), —NR^(5B)R^(5C), —C(O)R^(5D),        —C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A), —NR^(5B)SO₂R^(5A),        —NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D), —NR^(5B)OR^(5D),        —OCX^(5.1) ₃, —OCHX^(5.1) ₂, —OCH₂X^(5.1), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl or substituted or unsubstituted heteroaryl;    -   R⁶ is independently halogen, oxo, —CX^(6.1) ₃, —CHX^(6.1) ₂,        —CH₂X^(6.1), —CN, —N₃, —SO_(n6)R^(6A), —SO_(v6)NR^(6B)R^(6C),        —NHNR^(6B)R^(6C), —ONR^(6B)R^(6C), —NHC(O)NHNR^(6B)R^(6C),        —NHC(O)NR^(6B)R^(6C), —N(O)_(m6), —NR^(6B)R^(6C), —C(O)R^(6D),        —C(O)OR^(6D), —C(O)NR^(6B)R^(6C), —OR^(6A), —NR^(6B)SO₂R^(6A),        —NR^(6B)C(O)R^(6D), —NR^(6B)C(O)OR^(6D), —NR^(6B)OR^(6D),        —OCX^(6.1) ₃, —OCHX^(6.1) ₂, —OCH₂X^(6.1), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl or substituted or unsubstituted heteroaryl;    -   R⁷ is hydrogen, halogen, —CX^(7.1) ₃, —CHX^(7.1) ₂, —CH₂X^(7.1),        —CN, —N₃, —SO_(n7)R^(7A), —SO_(v7)NR^(7B)R^(7C),        —NHNR^(7B)R^(7C), —ONR^(7B)R^(7C), —NHC(O)NHNR^(7B)R^(7C),        —NHC(O)NR^(7B)R^(7C), —N(O)_(m7), —NR^(7B)R^(7C), —C(O)R^(7D),        —C(O)OR^(7D), —C(O)NR^(7B)R^(7C), —OR^(7A), —NR^(7B)SO₂R^(7A),        —NR^(7B)C(O)R^(7D), —NR^(7B)C(O)OR^(7D), —NR^(7B)OR^(7D),        —OCX^(7.1) ₃, —OCHX^(7.1) ₂, —OCH₂X^(7.1), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl or substituted or unsubstituted heteroaryl;    -   R⁸ is hydrogen, halogen, —CX^(8.1) ₃, —CHX^(8.1) ₂, —CH₂X^(8.1),        —CN, —N₃, —SO_(n8)R^(8A), —SO_(v8)NR^(8B)R^(8C),        —NHNR^(8B)R^(8C), —ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C),        —NHC(O)NR^(8B)R^(8C), —N(O)_(m8), —NR^(8B)R^(8C), —C(O)R^(8D),        —C(O)OR^(8D), —C(O)NR^(8B)R^(8C), —OR^(8A), —NR^(8B)SO₂R^(8A),        —NR^(8B)C(O)R^(8D), —NR^(8B)C(O)OR^(8D), —NR^(8B)OR^(8D),        —OCX^(8.1) ₃, —OCHX^(8.1) ₂, —OCH₂X^(8.1), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R⁹ is hydrogen, halogen, —CX^(9.1) ₃, —CHX^(9.1) ₂, —CH₂X^(9.1),        —CN, —N₃, —SO_(n9)R^(9A), —SO_(v9)NR^(9B)R^(9C),        —NHNR^(9B)R^(9C), —ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C),        —NHC(O)NR^(9B)R^(9C), —N(O)_(m9), —NR^(9B)R^(9C), —C(O)R^(9D),        —C(O)OR^(9D), —C(O)NR^(9B)R^(9C), —OR^(9A), —NR^(9B)SO₂R^(9A),        —NR^(9B)C(O)R^(9D), —NR^(9B)C(O)OR^(9D), —NR^(9B)OR^(9D),        —OCX^(9.1) ₃, —OCHX^(9.1) ₂, —OCH₂X^(9.1), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl, or when X² is        CR⁹, then R⁴ and R⁹ may optionally be joined to form a        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl; or when X² is        CR⁹ and X³ is CR¹⁰, then R⁹ and R¹⁰ may optionally be joined to        form a substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R¹⁰ is hydrogen, halogen, —CX^(10.1) ₃, —CHX^(10.1) ₂,        —CH₂X^(10.1), —CN, —N₃, —SO_(n10)R^(10A),        —SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C), —ONR^(10B)R^(10C),        —NHC(O)NHNR^(10B)R^(10C), —NHC(O)NR^(10B)R^(10C), —N(O)_(m10),        —NR^(10B)R^(10C), —C(O)R^(10D), —C(O)OR^(10D),        —C(O)NR^(10B)R^(10C), —OR^(10A), —NR^(1B)SO₂R^(1A),        —NR^(10B)C(O)R^(10D), —NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D),        —OCX^(10.1) ₃, —OCHX^(10.1) ₂, —OCH₂X^(10.1), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl; or when X² is        CR⁹ and X³ is CR¹⁰, then R⁹ and R¹⁰ may optionally be joined to        form a substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R⁴⁴ is hydrogen, —CX^(44.1) ₃, —CHX^(44.1) ₂, —CH₂X^(44.1),        —SO_(n44)R^(44A), —SO_(v44)NR^(44B)R^(44C), —C(O)R^(44D),        —C(O)OR^(44D), —C(O)NR^(44B)R^(44C), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl or substituted or unsubstituted heteroaryl;    -   R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D),        R^(3A), R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D),        R^(5A), R^(5B), R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D),        R^(7A), R^(7B), R^(7C), R^(7D), R^(7.2B), R^(8A), R^(8B),        R^(8C), R^(8D), R^(9A), R^(9B), R^(9C), R^(9D), R^(10A),        R^(10B), R^(10C), R^(10D), R^(44A), R^(44B), R^(44C), and        R^(44D) are independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃,        —CI₃, —COOH, —CONH₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl; R^(1B), R^(1C), R^(2B),        R^(2C), R^(3B), R^(3C), R^(4B), R^(4C), R^(5B), R^(5C), R^(6B),        R^(6C), R^(7B), R^(7C), R^(8B), R^(8C), R^(9B), R^(9C), R^(10B),        R^(10C), R^(44B), and R^(44C) substituents bonded to the same        nitrogen atom may optionally be joined to form a substituted or        unsubstituted heterocycloalkyl or substituted or unsubstituted        heteroaryl; and    -   X^(1.1), X^(2.1), X^(3.1), X^(4.1), X^(5.1), X^(6.1), X^(7.1),        X^(8.1), X^(9.1), X^(10.1), and X^(44.1) are independently —Cl,        —Br, —I or —F;    -   wherein at least one of X¹, X² and X³ is N.

Embodiment 8

The method of Embodiment 7, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

Embodiment 9

A method of treating a malignancy that is positive for Epstein BarrVirus (EBV), the method comprising administering to a subject in needthereof a therapeutically effective amount of a compound of formula (V):

or a pharmaceutically acceptable salt thereof.

Embodiment 10

The method of any one of embodiments 1 to 9, wherein the EBV positivemalignancy is Burkitt's lymphoma, Hodgkin's lymphoma, diffuse largeB-cell lymphoma, NK/T-cell lymphoma, cutaneous T-cell lymphoma,nasopharyngeal carcinoma, gastric cancer, vulvar squamous cellcarcinoma, salivary gland cancer, orbit choroidal melanoma, oradenocarcinoma consistent with pancreaticobiliary.

Embodiment 11

The method of embodiment 10, further comprising co-administering to asubject in need thereof a chemotherapeutic agent or anticancer agent.

Embodiment 12

The method of embodiment 11, wherein the chemotherapeutic agent oranticancer agent is an antiproliferative/antineoplastic drug, anantimetabolite, an antitumor antibiotic, an antimitotic agent, atopoisomerase inhibitor, a cytostatic agent, an estrogen receptor downregulator, an antiandrogen, a LHRH antagonist or LHRH agonist, aprogestogen, an aromatase inhibitor, an inhibitor of 5-alpha-reductase,an agent which inhibits cancer cell invasion, an inhibitor of growthfactor function, a farnesyl transferase inhibitor, a tyrosine kinaseinhibitor, a serine/threonine kinase inhibitor, an inhibitor of theepidermal growth factor family, an inhibitor of the platelet-derivedgrowth factor family, an inhibitor of the hepatocyte growth factorfamily; an antiangiogenic agent, a vascular damaging agent, an antisensetherapy agent, an anti-ras antisense agent, an gene therapy agent, animmunotherapeutic agent, or an antibody.

Embodiment 13

The method of embodiment 12, wherein the chemotherapeutic agent oranticancer agent is an anti-proliferative agent, a chemotherapeuticagent, an antimetabolite, an antimicrotubule agent, an alkylating agent,a platinum agent, an anthracycline, an antitumor antibiotic, atopoisomerase inhibitor, a purine antagonist, a pyrimidine antagonist, acell maturing agent, a DNA repair enzyme inhibitor, an enzyme thatprevents cell survival, a histone deacetylase inhibitor, a cytotoxicagent, a hormone, an antibody, an immuno-modulator, a Bcr-Abl kinaseinhibitor, a hormone agonist or antagonist, partial agonist or partialantagonist, a kinase inhibitor, surgery, radiotherapy, an endocrinetherapy, a biological response modifier, a hyperthermial agent, acryotherapeutic agent, an immuomodulating agent, an agent to attenuateany adverse effects, a spindle poison, a podophyllotoxin, an antibiotic,or a nitrosourea.

Embodiment 14

The method of embodiment 13, wherein the antimetabolite is 5-fluorouracil, methotrexate, azacitidine, decitabine, fludarabine orcytarabine.

Embodiment 15

The method of embodiment 13, wherein the antimicrotubule agent is avinca alkaloid or a taxane.

Embodiment 16

The method of embodiment 13, wherein the alkylating agent ismechlorethamine, chlorambucil, cyclophosphamide, melphalan, carmustine,lomustine, ifosfamide, carmustine, busulfan, cyclophosphamide,dacarbazine, ifosfamide, bischloroethylnitrosurea or hydroxyurea.

Embodiment 17

The method of embodiment 13, wherein the platinum agent is cisplatin,carboplatin, oxaliplatin, satraplatin (JM-216) or CI-973.

Embodiment 18

The method of embodiment 12, wherein the chemotherapeutic agent oranticancer agent is an antibody.

Embodiment 19

The method of embodiment 12, wherein the chemotherapeutic agent oranticancer agent is an immunomodulating agent.

Embodiment 20

Use of the compound of any one of embodiments 1 to 9 to treat amalignancy that is positive for Epstein Barr Virus (EBV).

Embodiment 21

Use of the compound of any one of embodiments 1 to 9 in the manufactureof a medicament to treat a malignancy that is positive for Epstein BarrVirus (EBV).

Embodiment 22

A method of treating a malignancy that is positive for Epstein BarrVirus (EBV), the method comprising administering to a subject in needthereof a therapeutically effective amount of a C—C chemokine receptortype 4 (CCR4) modulator.

Embodiment 23

The method of embodiment 22, wherein the CCR4 modulator is a compounddisclosed in Hobbs et al, US 2012/0015932; Cheshire et al, US2010/0144759; Cheshire et al, US 2008/0293742; Cheshire US 2006/0189613;Mete et al, US 2006/0128723; Harrison et al, US 2006/0122195; Habashitaet al, US 2006/0004010; Collins et al, US 2004/0039035; Collins et al,US 2003/0018022; Collins et al, US 2002/0173524; Dairaghi et al, US2002/0132836; U.S. Pat. Nos. 5,300,498; 6,509,357; US 2003/149018; WO01/005758; WO 03/051876; WO 97/042174; WO 2006/101456; WO 2007/065683;WO 2007/065924; WO 2007/115231; WO 2008/045529; WO 2008/094575; WO2008/094602; WO 2010/118367; and WO 2013/082429.

Embodiment 24

The method of embodiment 22, wherein the CCR4 modulator is an antibody.

Embodiment 25

The method of embodiment 24, wherein the CCR4 modulating antibody is onedisclosed in Marasco et al. US 2017/0290911; Lin et al. US 2017/0088627;Marasco et al. US 2016/0185865; Ishii et al. US 2015/0147321; Shitara etal. US 2013/0295045; Wu et al. US 2007/0031896; Shitara et al. US2007/0020263; and Iida et al. US 2005/0287138.

INCORPORATION BY REFERENCE

All disclosures (e.g., patents, publications, and web pages) referencedthroughout this specification are incorporated by reference in theirentireties.

The present disclosure has been described in connection with certainembodiments and examples; however, unless otherwise indicated, theclaims should not be unduly limited to such specific embodiments andexamples disclosed.

What is claimed is:
 1. A method of treating a malignancy that ispositive for Epstein Barr Virus (EBV), the method comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: L⁷ is a bond,unsubstituted alkylene or unsubstituted heteroalkylene; R^(3.2) andR^(3.3) are independently halogen; R⁴ is —CX^(4.1) ₃, —CN, orunsubstituted C₁-C₄ alkyl; R⁷ is hydrogen, —C(O)R^(7D),—C(O)NR^(7B)R^(7C), OR^(7A), —NR^(7B)C(O)R^(7D), substituted orunsubstituted alkyl or substituted or unsubstituted heteroalkyl; R^(7A),R^(7B), R^(7C), and R^(7D) are independently hydrogen or substituted orunsubstituted alkyl; and X^(4.1) is —Cl, —Br, —I or —F.
 2. The method ofclaim 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 3. The method of claim 1,wherein the EBV positive malignancy is Burkitt's lymphoma, Hodgkin'slymphoma, diffuse large B-cell lymphoma, NK/T-cell lymphoma, cutaneousT-cell lymphoma, nasopharyngeal carcinoma, gastric cancer, vulvarsquamous cell carcinoma, salivary gland cancer, orbit choroidalmelanoma, or adenocarcinoma consistent with pancreaticobiliary.
 4. Themethod of claim 3, further comprising co-administering to a subject inneed thereof a chemotherapeutic agent or anticancer agent.
 5. The methodof claim 4, wherein the chemotherapeutic agent or anticancer agent is anantiproliferative/antineoplastic drug, an antimetabolite, an antitumorantibiotic, an antimitotic agent, a topoisomerase inhibitor, acytostatic agent, an estrogen receptor down regulator, an antiandrogen,a LHRH antagonist or LHRH agonist, a progestogen, an aromataseinhibitor, an inhibitor of 5-alpha-reductase, an agent which inhibitscancer cell invasion, an inhibitor of growth factor function, a farnesyltransferase inhibitor, a tyrosine kinase inhibitor, a serine/threoninekinase inhibitor, an inhibitor of the epidermal growth factor family, aninhibitor of the platelet-derived growth factor family, an inhibitor ofthe hepatocyte growth factor family; an antiangiogenic agent, a vasculardamaging agent, an antisense therapy agent, an anti-ras antisense agent,an gene therapy agent, an immunotherapeutic agent, or an antibody. 6.The method of claim 5, wherein the chemotherapeutic agent or anticanceragent is an anti-proliferative agent, a chemotherapeutic agent, anantimetabolite, an antimicrotubule agent, an alkylating agent, aplatinum agent, an anthracycline, an antitumor antibiotic, atopoisomerase inhibitor, a purine antagonist, a pyrimidine antagonist, acell maturing agent, a DNA repair enzyme inhibitor, an enzyme thatprevents cell survival, a histone deacetylase inhibitor, a cytotoxicagent, a hormone, an antibody, an immuno-modulator, a Bcr-Abl kinaseinhibitor, a hormone agonist or antagonist, partial agonist or partialantagonist, a kinase inhibitor, surgery, radiotherapy, an endocrinetherapy, a biological response modifier, a hyperthermial agent, acryotherapeutic agent, an immuomodulating agent, an agent to attenuateany adverse effects, a spindle poison, a podophyllotoxin, an antibiotic,or a nitrosourea.
 7. The method of claim 6, wherein the antimetaboliteis 5-fluoro uracil, methotrexate, azacitidine, decitabine, fludarabineor cytarabine.
 8. The method of claim 6, wherein the antimicrotubuleagent is a vinca alkaloid or a taxane.
 9. The method of claim 6, whereinthe alkylating agent is mechlorethamine, chlorambucil, cyclophosphamide,melphalan, carmustine, lomustine, ifosfamide, busulfan, dacarbazine,bischloroethylnitrosurea or hydroxyurea.
 10. The method of claim 6,wherein the platinum agent is cisplatin, carboplatin, oxaliplatin,satraplatin (JM-216) or CI-973.
 11. The method of claim 5, wherein thechemotherapeutic agent or anticancer agent is an antibody.
 12. Themethod of claim 5, wherein the chemotherapeutic agent or anticanceragent is an immunomodulating agent.
 13. Use of the compound of claim 1to treat a malignancy that is positive for Epstein Barr Virus (EBV),wherein the use comprises administering to a subject in need thereof atherapeutically effective amount of the compound of formula (I).
 14. Themethod of claim 1, wherein R⁴ is —CX^(4.1) ₃, —CN, or methyl.
 15. Themethod of claim 5, wherein the chemotherapeutic agent is pembrolizumab.